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University City is the easternmost portion of West Philadelphia, encompassing several Philadelphia universities. It is situated directly across the Schuylkill River from Center City. The University of Pennsylvania was instrumental in coining the name University City as part of a 1950s urban renewal and gentrification effort. University City is also home to Drexel University and the University City campus of Saint Joseph's University. The eastern side of University City contains the Penn and Drexel campuses, several medical institutions, independent centers of scientific research, 30th Street Station, one of the nation's busiest passenger train stations, Cira Centre, and Cira Centre South. The western side contains Victorian and early 20th century housing stock and is primarily residential.

The University City neighborhood consists of 25,183 males and 25,783 females. The area population has grown 2.6% from 2000 to 2014 and 0.7% from 2010 to 2014. There are 32,935 white collar workers and 11,555 blue collar workers.

Before the European colonization of the Americas, Philadelphia was home to the Lenape people, whose land, known as Lenapehoking, covered much of the Atlantic coast from western Connecticut to Delaware. In 1677, William Warner purchased from the local Indian tribe and named it Blockley after his native parish in England. Blockley Township had a poor reputation in the 19th century. "It was an ideal hideout for shadowy characters and evil doers who crossed the river in skiffs after a thieving or smuggling job south of the city. As late as 1850 it was considered hazardous to be abroad alone in this area." The Blockley Almshouse, later known as Philadelphia General Hospital, was there. Though Blockley was founded five years before Philadelphia, people soon referred to it as "West Philadelphia". Later, parts of Blockley were carved out to form the District of West Philadelphia. In 1735, Andrew Hamilton, a "Philadelphia Lawyer", purchased in Blockley Township. The area came to be known as Hamilton Village and The Woodlands, a sprawling botanical garden and mansion, was built there. The gardens is now the Woodlands Cemetery, while much of the rest of Hamilton Village is covered by the 40th Street retail corridor. A small section on the northern side of this area was once known as Greenville. Situated near Lancaster Ave., Powelton Ave., and Market St., Greenville served as a waypoint for travelers and cattle drivers, and many taverns and inns were established. Later, the area expanded in all directions with many German immigrants and offered much more than simple taverns. By the mid 20th century, the Greenville area had changed again, to a neighborhood that was colloquially referred to as the Black Bottom, signifying the neighborhood's racial and economic status. Much of this neighborhood was destroyed as part of a gentrification plan in the 1960s. The arrival of electrified streetcars in the 1890s kick started development to the west of 43rd Street, and bridges and a tunnel in the first decade of the 20th century allowed people to easily commute into Center City. This led to rapid development within the borders of University City and far beyond. It was around this time that the "local" neighborhood names like Spruce Hill and Cedar Park were established. In the mid 1950s, two realtors and Penn graduates coined the name "University City" in an attempt to attract Penn faculty back to the neighborhoods near Penn. Within these boundaries are the local neighborhoods of Cedar Park, Garden Court, Spruce Hill, Squirrel Hill, Powelton Village, Walnut Hill, and Woodland Terrace. The boundaries also encompass several historic districts, including the West Philadelphia Streetcar Suburb Historic District, and the ZIP codes 19104, 19139, and 19143.

University City has a history of strained town and gown relations, particularly with the University of Pennsylvania ("Penn" for short), the city's largest private employer and the second largest private employer in Pennsylvania. During the 1960s, Penn led a series of gentrification and redevelopment programs that have changed the character of the area. Opened in 2001, the Penn Alexander is a neighborhood public elementary school which Penn helped to build and subsidizes. It is open to students inside a "catchment" defined by the School District of Philadelphia and Philadelphia City Council. The Penn Mortgage program is a grant made by Penn to any of its staff towards the purchase of a home in West Philadelphia or to be used for the improvement of any staff that currently owns a home in West Philadelphia. The university is also an active participant in branding the area as "University City", with its logo showing up next to the name on signs and bridges (not including street signs directing to University City, which are erected by the city, state, and federal governments). For decades, 40th Street was generally considered the "invisible campus boundary" between the residential neighborhoods to the west and the Penn campus to the east. In recent years, the "Penn bubble" is said to have expanded further west.

As part of the Housing Act of 1949, Congress established the "Slum Clearance and Community Development and Redevelopment" program, commissioning federal funds to "assist local communities in eliminating their slums and blighted areas and in providing the maximum opportunity for the redevelopment of project areas by private enterprise." A few years prior, in 1945, the Redevelopment Authority of the City of Philadelphia (RDA) was formed with the power to acquire and redevelop land through condemnation proceedings. This power to take land reached University City when The West Philadelphia Corporation (WPC) was formed in 1959 by a group of local institutions including Penn. A 1965 map shows the "units" identified for redevelopment.

Much of what is now the center of Penn's campus, including Locust Walk and Superblock, was part of the redevelopment of Unit 4. The key purpose of creating these high rises was to accommodate 3,500 more students at the university. The whole superblock project and especially the high rise design were widely criticized, but this view is not held by everyone.

WPC also guided several other redevelopments that directly benefited Penn and Drexel. and grounds for a World's fair have been scrapped, but a new plan called "30th Street Station District" is in the works. The Schuylkill Yards project is also in this area. A small part of this area was used to build the Cira Centre, a 29 story, crystal shaped office tower with distinctive LED lighting visible at night.

Beginning in 1991, Penn publicly expressed official interest in acquiring the to the southeast of its campus occupied by the Philadelphia Civic Center complex. After the opening of the Pennsylvania Convention Center in 1992, the Civic Center was mostly unused. In 1998, a City Council resolution was put forth to turn over much of this property to Penn and CHOP. The initial plans were not fully developed, but did not call for the demolition of Convention Hall, the location of several historic events. By 2005, plans had been expanded and the whole site, including Convention Hall, was slated for demolition to make way for a new clinical care facility attached to the hospital. Many local preservationists were opposed to this. Some were mollified by an exhaustive study commissioned by Penn to find alternate uses for the buildings and demolition continued. The last remaining building in the complex, Pennsylvania Hall, was demolished on March 3, 2007. Penn's Perelman Center for Advanced Medicine was officially opened on October 2, 2008.

In 2007, Penn bought between its campus and the Schuylkill river, an area formerly occupied by the United States Postal Service known as the Postal Lands. (A 1994 map shows the area before the GE building was refurbished into the Left Bank and the Cira Centre was built.) Penn repurposed the Postal Lands into a new high rise office and residential complex, Cira Centre South, and a public park with University athletic facilities, Penn Park. In addition, the former post office building has been turned into office space for the IRS. Penn Park opened in September 2011 as a new urban park that stretches from Walnut Street to South Street featuring a fabric of tightly interwoven recreational and athletic components. The project also includes underground cisterns that collect and repurpose rainwater. Cira Centre South was developed by Brandywine Realty Trust and completed in 2016. Two new towers replaced a one time truck annex for the Post Office and now include the headquarters for the FMC Corp., a parking garage with a green roof open to the public, an apartment building, and street level retail. The 49 story FMC Tower in this complex is the tallest building in University City.

University City District (UCD) is the name of a private, non profit organization created by the University of Pennsylvania and other local institutions in 1997 in an effort to provide University City with additional safety, cleanup, and marketing services as well as help in coordinating district initiatives.

In 2007, the University City District released a new edition of its University City Report Card, based on 2006 demographic statistics. The report said the area had 45,787 people living in 16,625 households, 29% of which are classified as "family" households and the rest as "non family". The average household size was two people, whose median age was 23.8 years. Median household income was $23,749; median "family" household income was $40,042. 8.1% of households had incomes of $100,000 or more and 35.2% had incomes of less than $15,000. The racial makeup of University City was about 42% Black, 35% White, 18% Asian/Pacific Islander, 4% Hispanic, with the remainder not classified. The report said local businesses employed 63,878, with educational services employing 53.1% of them and health care services 21%. The largest employers were Penn, with 13,239 employees; Penn Health, 11,136; CHOP, 6,855; Drexel Main, 2,706; AMTRAK, 2,551; and the VA, 2,100. The median price of homes purchased in 2006 was $312,000, up 22% from 2005. The average monthly rent for a studio apartment was $667; a one bedroom apartment, $823; and a two bedroom apartment, $1,174.

Neighborhood Bike Works: Donates bicycles and helmets to local kids. Offers training in bicycle repair. Philadelphia Elwyn: Care for the mentally disabled. Philadelphia Ronald McDonald House: A "home away from home" for families of seriously ill children receiving treatment at nearby hospitals.

With its compact development and high proportion of students, many people can and do walk and bicycle around, to, and from University City. Additionally, multiple highway, rail, and bus routes pass through University City, including major intercity and regional routes.

The most prominent highway through the region is the Schuylkill Expressway (I 76). I 676 from New Jersey and Center City Philadelphia terminates in University City at I 76. US 30 follows I 76 and I 676. US 13 and PA 3 follow local streets. Of historical note are the Philadelphia and Lancaster Turnpike and Baltimore Pike, now known as Lancaster Ave and Baltimore Ave. Additionally, Philadelphia's historic Market Street runs through the area, where it is known as the Avenue of Technology. There are several bus lines that serve University City. SEPTA City Transit Division surface routes 21, 30, 40, 42, 78 are active here, as is LUCY, the "Loop through University CitY". Regional bus operators Megabus and BoltBus offer service from near 30th & JFK to NYC.

The area is served by four distinct types of passenger rail transportation: intercity, regional, metro, and trolley. Amtrak's Northeast Corridor and Keystone Corridor intercity routes, as well as all of the SEPTA Regional Rail routes and NJT's Atlantic City Line, include a stop at 30th Street Station. SEPTA's Market–Frankford Line (MFL, also known as "the El") and Subway–Surface Trolley Lines stop at the adjacent 30th Street subway station. There are also several other SEPTA stations in University City, including two more Regional Rail stations: Penn Medicine and 49th St; three more MFL stations: 34th St., 40th St. and 46th St.; three more underground trolley stations: 33rd St., 36th St., 37th St.; and two trolley portals: 36th St. and 40th St. West of the portals, the trolleys run on the streets. An elevated freight line also runs above 31st Street, with connections to several other lines at the Zoo and Arsenal Interlockings, to the north and south, respectively.