The Gooderham and Worts Distillery was founded in 1832 and by the late 1860s was the largest distillery in the world. Once providing over 2 million US gallons (7,600,000 L) of whisky, mostly for export on the world market, the company was bought out in later years by rival Hiram Walker Co., another large Canadian distiller. Its location on the side of the Canadian National Railway mainline and its proximity to the mouth of the original route of the Don River outlet into Lake Ontario created a hard edge which separated the district from neighbouring communities. These did, however, allow for a facilitated transport connection to the rest of Canada and the world and acted as Toronto's domination as an industrial centre or transshipping hub.
With the deindustrialization of the surrounding area in the late 20th century, and the winding-down of the distillery operations, the district was left increasingly derelict. Surrounding industrial and commercial buildings and structures were often demolished, leaving the former distillery surrounded primarily by empty lots. Nonetheless, the closing of the remaining distillery operations in 1990 created redevelopment and investment opportunities for a district that contained the largest and best preserved collection of Victorian-era industrial architecture in North America. The Distillery District was designated as a National Historic Site, and has been protected under the Ontario Heritage Act since 1976. It was listed by National Geographic magazine as a "top pick" in Canada for travellers.
The economic recession of the early 1990s, however, and the resulting crash in residential condominium prices and office lease rates in downtown Toronto, delayed efforts to revitalize the district. Nonetheless, two residential condominium buildings were constructed on the periphery of the district during the late 1990s.
While the site awaited redevelopment and reinvestment, the district's ambiance began to attract numerous film shoots. Since 1990, the site has served as a location for over 800 film and television productions.
In 2001, the site was purchased by Cityscape Holdings Inc., which transformed the district into a pedestrian-orientated area. Work was completed and the district reopened to the public by 2003. The new owners refused to lease any of the retail and restaurant space to chains or franchises, and accordingly, the majority of the buildings are occupied with boutiques, art galleries, restaurants, jewellery stores, cafés, and coffeehouses, including a well-known microbrewery, the Mill Street Brewery. The upper floors of a number of buildings have been leased to artists as studio spaces and to office tenants with a "creative focus". A new theatre, the Young Centre for the Performing Arts, has opened on the site and serves as the home of the Soulpepper Theatre Company and the drama productions of nearby George Brown College. There are plans to develop residential condominiums, offices, and more retail space on the vacant lands that surround the district.
New condominium developments will be located at the south-east corner of the neighbourhood, bordering on Cherry Street and Tank House Lane.
The Pan American Games' Athletes' Village was built in the area in 2015, in conjunction with an extension to the streetcar network constructed along Cherry Street. After the games, the athletes village was converted to townhouses, condos, affordable housing, and retail space.