Cermak was elected president of the Cook County Board of Commissioners in 1922, chairman of the Cook County Democratic Party in 1928, and mayor of Chicago in 1931. In 1928 he ran for the United States Senate and was defeated by Republican Otis F. Glenn, receiving 46% of the vote.
His mayoral victory came in the wake of the Great Depression and the deep resentment many Chicagoans had of Prohibition and the increasing violence resulting from organized crime's control of Chicago, typified by the St. Valentine's Day Massacre.
Cermak was shot while being at a Democratic Party convention for Franklin D. Roosevelt on March 6, 1933. Later doctors said he would have lived if he had never had colitis, aged 59.Her daughter, Helena, would later marry future Governor of Illinois Otto Kerner, Jr.