Born on May 24, 1965, and raised in a working-class neighborhood on Chicago’s South Side, Reilly became interested in theater early on and debuted in his first stage production at the age of eight. As a teen, he migrated between school cliques, but felt most at home in school plays and regional theatres – with his older brothers “taking care of” anyone who had a problem with their kid brother singing in musicals. After graduating from an all-boys Catholic school, Reilly was accepted into Chicago’s DePaul University, home of the famed Goodman School of Drama. The quick-witted and admittedly soft-hearted actor still had not considered the theater as a career option, but after several years in the drama program, he decided there was probably nothing else he was better suited to do, so he would try to make a living in the Windy City’s unusually fertile theater scene.

Reilly made his professional debut with Chicago's Organic Theatre, where he also wrote and directed a series of monologues called "Walkin' the Boogie.” He graduated from DePaul in 1987 with a BFA in Drama and was asked to join the prestigious Steppenwolf Theatre Company, where he appeared in "Othello" and was part of the 1988 premiere of “The Grapes of Wrath," alongside fellow future star Gary Sinise. Not long after the well-received run of “Grapes,” Reilly’s agent suggested he send an audition tape for an upcoming Brian De Palma film. Reilly had never been in front of a camera or considered doing film, but he obliged, finding himself flown to Southeast Asia – also marking the first time he’d ever left Chicago or been on a plane – to shoot a minor walk-on as a Vietnam War soldier in “Casualties of War” (1989).

Once on the set, Reilly was immediately bumped up to a supporting role. During a rehearsal, he stepped in to play stand-in to an absent 80-year-old Vietnamese man, leaving both director De Palma and star Sean Penn taken by Reilly’s stage-quality commitment to an offhand request. He was bumped up again to a major supporting role opposite Sean Penn. The same week, he met his future wife, Penn’s assistant Alison Dickey. Within seven days, Reilly had unwittingly launched his future, both professional and personal. He immediately re-teamed with Penn to play a young monk in "We're No Angels" (1989), before debuting on Broadway with Steppenwolf’s production of “Grapes of Wrath,” which went on to earn a Tony Award for Best Play.

Reilly began to appear in a steady stream of supporting roles, playing Tom Cruise's pit crew chief in the NASCAR drama, "Days of Thunder” (1990) and more memorably alongside respected thespians Penn and Gary Oldman in the Irish mob tale, "State of Grace" (1990). The newcomer was also given a vote of confidence when he was cast in Woody Allen’s German expressionist tribute "Shadow and Fog" (1992). Reilly gave a classic performance as an aspiring small-town fry cook and friend of Johnny Depp's title character in "What's Eating Gilbert Grape" (1993), before landing a co-starring role with Kevin Bacon as a pair of deceptively friendly outlaws in "The River Wild" (1994).

By 1995, ardent moviegoers were beginning to recognize Reilly as “that guy” — that guy who looked and acted like a real person and balanced big stars with his rich, subtle characterizations in minor roles. That year, he appeared in the highly-acclaimed films "Dolores Claiborne” and "Georgia” – in which he was especially convincing in the latter as the drug-addicted drummer of a local bar band. However, it was the friendship he formed with then-unknown director Paul Thomas Anderson that caused the actor's film career to blossom. Anderson had apparently seen every film Reilly had done to date, and recognized the actor’s underused talent. He cast Reilly alongside Philip Baker Hall as a gambler’s protégé in his directorial debut, "Hard Eight" (1996). Reilly and the film received positive reviews, but the indie had a limited release that did not reach a large audience. The same could not be said for Anderson’s next outing.

Following their auspicious beginning, Anderson wrote a role for Reilly in his next film, “Boogie Nights,” (1997). Anderson scored a commercial and critical hit with this stylized tale about the rise and fall of a John Holmes-like star (Mark Wahlberg) during porn’s last days before video. Reilly's performance as fellow porn star and aspiring magician, Reed Rothchild, was a standout among a powerful ensemble cast that also included Philip Seymour Hoffman, Julianne Moore and Heather Graham. With this role, Reilly’s profile enjoyed a considerable raise, leading director Terrence Malick to tap him to join the ensemble of the Oscar-nominated World War II drama, “The Thin Red Line” (1998) – a film that Hollywood’s best actors were all scrambling to be a part of. In 1999, Reilly again played a custom-made role given him by Anderson as a lonely police officer in "Magnolia.” The highly-analyzed film was revered by some critics and hailed as too overwrought by others, but it was definitely one of the most talked-about and nominated films of the year, with Reilly serving as one of its most grounding forces.

Reilly continued to nab supporting roles opposite Hollywood's top stars, playing a major league catcher in Kevin Costner's "For Love of the Game" (1999) and exploring a different world of male dynamics aboard a doomed boat in the blockbuster, “The Perfect Storm” (2000) co-starring George Clooney and Mark Wahlberg. He returned to Broadway the same year in Sam Shepard’s “True West,” with Reilly and co-star Philip Seymour Hoffman both receiving Tony nominations for their portrayal of feuding brothers. Then known as two of the best supporting actors of their generation, as well as favorites of Paul Thomas Anderson, the untraditional-looking leading men displayed their extraordinary range by alternating their roles throughout the show's four-month run. Film directors who had been reluctant to entrust lead roles to the two outstanding actors began to rethink their position.

In the wildly entertaining ensemble indie, “The Anniversary Party” (2001), Reilly earned an Independent Spirit nomination for his role as a partygoer whose foolish accident triggers near-death angst in his fellow guests. He followed up with another lesser-seen gem, “The Good Girl” (2002), playing a loser pothead house painter and spouse of discount store checkout girl, Jennifer Aniston. In 2002, Reilly surfaced in three of year’s five Oscar nominees for Best Film. In “The Hours,” he was riveting as the clean-cut, controlling spouse of Julianne Moore. He transformed into poor and hapless husband Amos Hart opposite Renee Zellweger in the musical "Chicago," where his gentle charm may not have taken audiences by surprise, but his vocal chops were a revelation that earned him an Academy Award nomination for Best Supporting Actor. Finally, Reilly was tapped to play a corrupt copper in Martin Scorsese's bloody epic about Irish gangsters, "The Gangs of New York." Few actors enjoyed that kind of Oscar-caliber trifecta in one year.

Reilly was enjoying the best of both worlds — steady acting work in quality film productions and a level of anonymity that allowed him to continually recreate himself, without battling the distraction of a public persona. He returned to the musical stage, this time in Boston, for a starring role as lonely butcher “Marty,” reviving a role made famous onscreen by Ernest Borgnine and earning excellent reviews. Onscreen, he was entrusted in his first truly starring role in “Criminal” (2004), a remake of the Argentinean hit “Nine Queens,” which followed con man Reilly and a grifter protégé (Diego Luna) during 24 hours in Los Angeles. In “The Aviator” (2004), Scorsese’s critically hailed epic about maverick billionaire Howard Hughes (Leonardo DiCaprio), Reilly portrayed Noah Dietrich, Hughes’ right-hand man and protector of his disintegrating public image. Never failing to surprise with his versatility, he went on to play half of a western music duo in Robert Altman’s Lake Wobegon chronicle, “A Prairie Home Companion” (2006).

One of his most mainstream, high profile appearances was custom made for Reilly’s sympathetic everyman charm, co-starring with Will Ferrell as the loyal, left-in-the-dust best friend in “Talladega Nights: The Ballad of Ricky Bobby” (2006). Reilly’s winning comic performance led to first billing in Jake Kasdan and Judd Apatow’s “Walk Hard: The Dewey Cox Story” (2007). The riotous rock biopic parody featured Reilly and his fantastic vocal versatility as he chronicled the life of a fictional singer through decades of musical trends, tossing off Roy Orbison falsetto, Johnny Cash baritone, and the classic nasal whine of Bob Dylan with equal genius. His performance was so impressive, he earned a Golden Globe nomination for Best Actor in a Musical or Comedy. Continuing with his resounding success in broad comedies, Reilly would reteam with Ferrell and director Adam McKay in “Step Brothers” (2008).