While Baltimore has been a major U.S. seaport since the 1700s, the historically shallow water of the Inner Harbor (prior to manipulation through dredging) was not conducive to large ships or heavy industry, most of which was concentrated in Locust Point, Fell's Point, and Canton. The Inner Harbor was chiefly a light freight commercial port and passenger port until the 1950s, when economic shifts ended both the freight and passenger use of the Inner Harbor, such as the Old Bay Line's steamers. Rotting warehouses and piers were eventually torn down and replaced by open, grass-covered parkland that was used for recreational purposes and occasional large events, such as city fairs and the significant 1976 bicentennial visit of tall ships. This initial renewal of the harbor area and its continued transformation into a major cultural and economic area of the city was spearheaded by Baltimore Mayor Thomas J. D'Alesandro, Jr. (1947-1959). Harborplace, the waterfront festival marketplace, officially opened on July 1, 1980. Since being reincarnated as a cultural hub, the Inner Harbor has become the home to many tourist attractions. The two anchor attractions, in addition to Harborplace, are the National Aquarium in Baltimore and the Maryland Science Center.

In recent years, the area along the waterfront to the east of the Inner Harbor (in the direction of Fells Point and Little Italy) has been developed with condominiums, retail space, restaurants, and hotels; this ongoing project is known as Inner Harbor East (or simply HarborEast).

While little development-appropriate land remains around the Inner Harbor, what land is available has attracted much interest and many plans, many of which have never been realized. In recent years, there has been a decided push by developers to construct projects on the remaining parcels. The ongoing, proposed, and recently completed projects include many mixed-use developments incorporating office space, street-level retail, and condominiums as well as some hotel projects.

Recent or proposed projects include Lockwood Place, a mixed-use project on Pratt St. between Market Pl. and Gay St. featuring Best Buy, Filene's Basement, Panera Bread, Famous Footwear, and P.F. Chang's; the Ritz Carlton Residences, a condominium project on Key Hwy. at the southeast corner of the Inner Harbor; and 10 Inner Harbor, a proposed mixed-use project at southwest corner of Light and Conway Sts. that includes a 59-story tower, which would be the tallest building in Baltimore (a title currently held by the Legg Mason Building).

Downtown Baltimore is the section of Baltimore traditionally bounded by Martin Luther King, Jr. Boulevard to the west, Mt. Royal Avenue to the north, President Street to the east and the Inner Harbor area to the south. It consists of four neighborhoods: Westside, City Centre, Inner Harbor, and Camden Yards. It is the focal point of business in the Baltimore metropolitan area with over 100,000 employees. It has also increasingly become a heavily populated neighborhood with over 37,000 residents and new condominiums and apartment homes being built steadily.

Fell's Point is home to a variety of shops, restaurants, coffee bars, music stores, and over 120 pubs. Located on the harbor and famous for its maritime past, it now boasts the greatest concentration of pubs/bars in the city. This waterfront community is a much-visited location in Baltimore, accessible by water taxi, freeway, and several bus lines. The neighborhood has also been the home of large Polish, Irish, and Mexican-American populations throughout its history. In recent years a steadily increasing numbers of middle to upper middle income residents have moved into the area, driving up property values. Fell's Point is one of several areas in and around Baltimore that are listed on the National Register of Historic Districts.

Situated just east of the Inner Harbor, it has one of the city's popular restaurant districts.  It is so named because of the large number of Italian immigrant families that moved into the area during the 20th century. The neighborhood is still home to a large and active Italian ethnic community. Located near newly desirable neighborhoods like Fells Point, Upper Fells Point and Harbor East, Little Italy's housing market is very hot, not least because turnover is low in the tight-knit community. Little Italy is also notable as one of the safest neighborhoods in the city of Baltimore, as the neighborhood's reputation is such to not allow crimes against the residents caused by outside agitators.

Jonestown is a historical section of southeast Baltimore established in 1732 that was laid out on 10 acres (40,000 m2) dived into twenty lots on the east side of the Jones Falls. The district is a mix of industrial, commercial and residential buildings. In the last half of the 20th century, Jonestown has shifted from a predominantly Eastern European and Jewish neighborhood into a predominantly African American neighborhood. Public housing replaced many of the former rowhomes and townhouses throughout the area, though a historical presence is still felt. In the early 2000s, though, modern row housing resembling suburban townhouses replaced the public housing. Jonestown is home to Baltimore's central post office in addition to 8 Baltimore City Landmarks including the Flag House and the Phoenix Shot Tower, both Registered National Historic Landmarks.

From early in the history of the city, the hill was a public gathering place and civic treasure. The hill itself was given the name in 1789 after serving as the location for the end of a parade and a following civic celebration of the ratification of the new "Federal" constitution of the United States of America. For much of the early history of Baltimore, the hill was know as Signal Hill because it was home to a maritime observatory serving the merchant and shipping interests of the city by observing the sailing of ships up the Patapsco River and signalling their impending arrival to downtown businesspeople.

Mount Vernon is located just north of downtown. Designated a National Landmark Historic District and a city Cultural District, it is one of the city's oldest neighborhoods and originally was home to the city's most wealthy and fashionable families. The name derives from the Mount Vernon home of George Washington; the original Washington Monument, a massive pillar commenced in 1815 to commemorate the first president of the United States, is the defining feature of the neighborhood.

Hampden was originally settled as a residential community for workers at the mills that sprung up along the Jones Falls; its first residents were in place well before the area was annexed to Baltimore City in 1888. Many of its residents came to the area from the hill country of Kentucky, West Virginia, and western Pennsylvania, looking for work in the mills. This influx cemented the image of the neighborhood for the decades that followed as a white, working-class, socially conservative enclave. However, like most of Baltimore, Hampden declined somewhat during the economic troubles of the 1980s-90s, and is a much more moderate political climate in recent history.

In the 1990s the neighborhood, conveniently located vis-a-vis Johns Hopkins and downtown, and relatively safe when compared to other, more blighted areas of the city, was discovered by artists and other bohemians, who began the process of gentrification. Many of these artists were attracted by the 1987 creation of an artist studio and office space known as the Mill Centre, located in the southernmost region of Hampden between Falls Road and Mill Road. Over the past decade, housing prices in Hampden have skyrocketed, and the area's commercial center on a four block stretch of West 36th Street known as The Avenue, has seen trendy boutiques and restaurants occupy storefronts that had become vacant when poor economic conditions forced many of the Avenue's traditional retailers to close.