In January 1992, a consortium of nonprofits and universities presented the first St. Louis Film Festival in April 1992. The St. Louis Film Festival Inc. was then established as a Missouri not-for-profit corporation in July 1992 and received its 501(c)3 status from the IRS in April 1993. In 1998, the organization changed its name to the St. Louis International Film Festival to emphasize the event's international component. In 2002, the organization was renamed Cinema St. Louis (CSL) to reflect its commitment to year-round programming beyond the festival. Cinema St. Louis now presents six annual events and co-presents additional film-related programming throughout the year.

The organization's premier event is the St. Louis International Film Festival (SLIFF), held in November. Since 2003, CSL presents the Cinema for Students Program as part of SLIFF, offering free screenings to St. Louis-area elementary, middle, and high schools.

CSL has steadily increased its year-round presence with additional programming. Since 2002, CSL has annually presented the St. Louis Filmmakers Showcase, held in July, which highlights work made by filmmakers with St. Louis roots. In 2009, CSL launched an annual Classic French Film Festival, held in March. In 2008, CSL added the LGBTQ-focused QFest, held in April, to its lineup. In 2013, CSL inaugurated free summer Filmmaking Camps for teens 12-18. CSL added another annual event in 2014 when it became the St. Louis producer of the 48 Hour Film Project, held in June. In 2019, CSL introduced Golden Anniversaries, a fest that features films celebrating their 50th anniversaries.

CSL also holds individual screenings, film series, and educational programs throughout the year, frequently collaborating with other St. Louis organizations such as Citygarden, St. Louis Science Center, Washington University's Film & Media Archive, Webster University Film Series, St. Louis Public Library, and Missouri History Museum.

Between 25,000-31,000 patrons attend the international festival each year, and an additional 5,000-12,000 annually attend CSL’s other events.