In April 1955, Despres was elected to the Chicago City Council from the city's Hyde Park neighborhood. Serving until 1975, Despres gained fame as an independent Democrat, consistently opposing the policies of Chicago Mayor Richard J. Daley. Frequently on the short end of 49-1 votes, Despres became known as the "liberal conscience of Chicago." Because of his strong advocacy of civil rights and open housing, Despres also became known as "the lone Negro on the City Council," even though he is white and the council had six black alderman allied with the mayor.
Now 100 years old, Despres lives in Hyde Park and remains active in civic life. In 2005, he received the Benton Medal from the University of Chicago. While largely retired from the practice of law, Despres still maintains an office at the Chicago firm of Despres, Schwartz, and Geoghegan, managed by longtime colleague, Chicago labor lawyer Thomas Geoghegan.