He is a graduate of Fordham University and Albany Law School. He was a top aide to his father during his father's 1982 campaign for governor. He then joined the governor's staff as one of his father's top policy advisors, a position he filled on and off during his father's 12-year governorship. Cuomo became active in issues effecting the homeless and housing policy in New York during the 1980s and 1990s. He founded a non-profit organization focused on homeless and housing issues.

During the administration of former New York City Mayor David Dinkins, Cuomo served as Chairman of the New York City Homeless Commission, which was charged with developing policies to end the homeless crisis in the city and to develop more housing options. In 1993, he was appointed by President Clinton as an Assistant Secretary of Housing and Urban Development. He served as an assistant secretary until 1997, when he became HUD Secretary. While at HUD, Cuomo has been credited for reorganizing the department and with promoting the creation of more housing nationwide. In addition, Cuomo launched programs aimed at improving the economy in Upstate New York.

Cuomo was a candidate for the Democratic nomination for Governor of New York in 2002. Before the primary, however, he withdrew in favor of H. Carl McCall. Cuomo, however, remained on the ballot as the nominee of the Liberal Party. Cuomo previously served as head of the New York City Commission on the Homeless. Many observers expected him to run for Governor of New York again, as a candidate for the Democratic nomination in 2006, but Cuomo decided against a run when New York State Attorney General Eliot Spitzer entered the race in late 2004.

Cuomo is the son of former New York Governor Mario Cuomo. He and his ex-wife, Kerry Kennedy, have three daughters. The couple announced their less than amicable separation in 2003, and have subsequently divorced. The Cuomos' marital difficulties have been the subject of wide public scrutiny, given that a third party is involved.

Cuomo is a candidate for the Democratic nomination for Attorney General of New York in 2006; he may have had to run against his former brother-in-law, Robert F. Kennedy, Jr., in the Democratic primary, but on January 25, 2005, Kennedy announced that he would not seek the office, thus clearing the path for Cuomo.

Cuomo is listed as the frontrunner in public opinion polls and is poised to finish first in the May Democratic State Convention in Buffalo. His opponents for the nomination are former New York City Public Advocate Mark J. Green, former U.S. Attorney Denise O'Donnell, former White House Staff Secretary Sean Patrick Maloney, Assemblyman Richard Brodsky, and former lieutenant governor candidate Charles King. King was appointed by Cuomo as Regional HUD Director for New York, New Jersey, and the U.S. Virgin Islands and was Cuomo's running mate in the 2002 elections.