Shelly's career breakthrough as an Actress came when she was cast by independent filmmaker Hal Hartley as the lead in The Unbelievable Truth (1989) and Trust (1990). Trust was nominated for the Grand Jury Prize at the Sundance Film Festival, where Hartley's script tied for the Waldo Salt Screenwriting Award. Shelly also guest-starred in a number of television series including Law & Order, Oz and Homicide: Life on the Street, and played major roles in over two dozen off-Broadway plays, often at Manhattan's Workhouse Theater. In 2005 she appeared in the film Factotum starring Matt Dillon.
During the 1990s, Shelly had segued toward a behind-the-camera career. She wrote and directed 1999's I'll Take You There, in which she appeared along with Ally Sheedy. She won a U.S. Comedy Arts Festival Film Discovery Jury Award in 2000 for direction of the film, and Prize of the City of Setúbal: Special Mention, at the Festróia (Tróia International Film Festival) held in Setúbal, Portugal, for best Director. Her final work was writing, directing, co-set- and costume-designing, and acting in the film Waitress, starring Keri Russell and Nathan Fillion, which premiered at the 2007 Sundance Film Festival. Shelly's daughter, Sophie, has a cameo at the end of the film.
Shelly, who took her professional surname after her late father's given name, was married to Andy Ostroy, the chairman and CEO of the marketing firm Belardi/Ostroy. They had a daughter, Sophie (born 2003), who was two years old at the time of her mother's death. Shelly described herself as an "optimistic agnostic."
On November 6, 2006, the press reported the arrest of a 19-year-old construction worker, Diego Pillco, an Ecuadorian illegal immigrant who according to police had confessed on tape to attacking Shelly, and then staging the fake suicide by hanging her. Pillco's original version of what happened was that when Shelly asked if the noise could be kept down, he threw a hammer at her and, afraid she would make a complaint that might result in his deportation, followed her back to her apartment, where the petite 40-year-old hit him, and was killed by a fall during a struggle. Subsequently, Pillco gave a completely different account in which he said while on a break he had noticed Shelly returning to her apartment and followed her. After assaulting her and rendering her unconscious, he killed her by staging the fake suicide. The second version was consistent with the lack of dust on Shelly's shoes (which she was not wearing when found) and seemed to be a confession to murder, but prosecutors reportedly thought if charged with murder Pillco might return to his original account and a jury trial could find him guilty of a lesser charge. The medical examiner determined that Shelly was still alive when hanged. Pillco pleaded guilty to first-degree manslaughter and was sentenced to 25 years in prison without parole.
Shelly's film, Waitress, had been accepted into the 2007 Sundance Film Festival before her murder. The film, starring Keri Russell, Nathan Fillion, Cheryl Hines, Jeremy Sisto, Andy Griffith and Shelly herself, was bought during the festival by Fox Searchlight Pictures for an amount between $4 million and $5 million (news accounts on the actual amount vary), and the film realized a final box-office draw of more than $19 million. Waitress maintains an 89% "fresh" rating on Rotten Tomatoes.
Following his wife's death, Ostroy established the Adrienne Shelly Foundation, a non-profit organization that awards scholarships, production grants, finishing funds and living stipends through its partnerships with academic and filmmaking institutions NYU, Columbia University, Women in Film, IFP, AFI, Sundance Institute, Tribeca Film Institute and the Nantucket Film Festival. One of its grant recipients, Cynthia Wade, won an Academy Award in 2008 for Freeheld, a short-subject documentary which the Foundation helped fund. As part of its annual awards, the Women Film Critics Circle gives the Adrienne Shelly Award to the film that "most passionately opposes violence against women".
Ostroy also spearheaded a move to establish a memorial to his wife. On August 3, 2009, the Adrienne Shelly Garden was dedicated on the Southeast side of Abingdon Square Park in NYC at 8th Avenue and West 12th Street. It faces 15 Abingdon Square, the building where Shelly died.
According to an acquaintance, Pillco said after eight months he still owed a debt on the $12,000 he had paid to be smuggled into the US, and he lived in the basement of a building owned by his employer. One of Shelly's neighbors told reporters that Pillco's stare had made the neighbor feel uncomfortable when she walked past him. Shelly's husband sued contractor Bradford General Contractors, which had hired Pillco. The complaint alleged that Shelly would still be alive if the contracting firm had not hired him. Ostroy also sought to hold the owners and management of the building liable for Shelly's murder. According to a New York Post article, among other allegations, the complaint stated that "'Pillco was an undocumented immigrant...' as were his co-workers, and that "it was in Bradford General Contractors' interest not to have 'police and immigration officials [called] to the job site' because that would have ground their work to a halt". On July 7, 2011, the lawsuit was dismissed by Judge Louis York. The court determined that Ostroy had not established legal grounds to hold the contractor liable, writing "While this court sympathizes with [Ostroy's] loss, plaintiffs have not presented sufficient legal grounds upon which to hold Bradford ... liable for Pillco's vicious crime", and that there was likewise insufficient evidence presented to find that either the building's management agents or its owners "had reason to believe that Pillco was a dangerous person who should not have been allowed to work at the premises" in order to find them vicariously liable. Ostroy was said to be considering an appeal.
The musical Waitress, based on the motion picture written by Shelly, opened on August 1, 2015, at the American Repertory Theater (A.R.T.) at Harvard University. It was directed by Diane Paulus and featured a book by Jessie Nelson and music and lyrics by Sara Bareilles. It starred Jessie Mueller, winner of a Tony Award for her portrayal of Carole King in the musical Beautiful. After a sold out limited engagement, the show moved to Broadway, starting in previews March 25, 2016, and officially opening April 24, 2016.