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Falco was born in Brooklyn, New York, the daughter of Judith Anderson, an actress, and Frank Falco, a jazz drummer. Her father is Italian American and her mother Swedish American. Falco's siblings are Joseph, Paul and Ruth. Her uncle is novelist, playwright and poet Edward Falco, an English professor at Virginia Tech in Blacksburg. She was raised in Northport and West Islip, on Long Island. She has an adopted son named Anderson Falco and an adopted daughter named Macy Falco.

Falco graduated from Northport High School in 1981, after playing Eliza Doolittle in a production of My Fair Lady. She attended SUNY Purchase with fellow actors Stanley Tucci and Ving Rhames; she remains friends with both.

Her first big break in films was a small speaking role in the 1994 Woody Allen film Bullets Over Broadway. One reason she got the part was her friendship with former SUNY Purchase classmate Eric Mendelsohn, who at the time was assistant to Allen's costume designer, Jeffrey Kurland. Mendelsohn would go on to direct Falco in his feature film Judy Berlin, for which he won "Best Director" honors at the Sundance Film Festival. Falco in 2007.

Falco, The X-Files star Gillian Anderson, Ugly Betty star America Ferrera, and 30 Rock's Tina Fey are the only actresses to have received a Golden Globe, an Emmy and a SAG Award in the same year. Falco won these awards in 2003 for her performance as Carmela during the fourth season of The Sopranos. Prior to that, she was a regular performer on Oz. She also had recurring roles on Law & Order and Homicide: Life on the Street.

Falco has won three Emmys, two Golden Globes and five Screen Actors Guild Awards.

She appeared in the films Trust, Cop Land, Random Hearts, Freedomland, and John Sayles' Sunshine State, for which she received the Los Angeles Film Critics Award for "Best Supporting Actress". On Broadway, she appeared in the Tony Award-winning Side Man and in the revivals of Frankie and Johnny in the Clair de Lune opposite Stanley Tucci, and Night, Mother opposite Brenda Blethyn. She has also appeared as a guest star on the television shows 30 Rock and Will & Grace.

During the 2004 U.S. presidential election, Falco appeared in a 30-second television commercial on behalf of M.O.B. (Mothers Opposing Bush) in which she said "Mothers always put their children first. Mr. Bush, can you say the same?", referring to George W.Bush who was running for re-election.

Records show that she donated $1,000 to John Kerry's 2004 presidential campaign, $300 to the Democratic National Committee in 2004, and two separate sums of $1,000 and $300 to Hillary Clinton in 2005.

Falco has said she had past problems with alcohol and said she decided to become sober after "one particular night of debauchery". She said in an interview that it's hard to be around the hard-partying cast of The Sopranos; "This cast (of the Sopranos) in particular, they really love to hang out and party. They make it look like fun. And it was fun for me! They spend a lot more time without me than with me, by my own choice - I'm always invited, and I'm always there for two minutes and I leave, because I can't live in that world anymore. It's too dangerous".

She is also a breast cancer survivor.