He is the host and producer of the radio and television series This American Life and has participated in other NPR programs, including Morning Edition, All Things Considered, and Talk of the Nation.

After Glass received a grant from the MacArthur Foundation, he and Torey Malatia developed This American Life, which won a Peabody Award within its first six months and became nationally syndicated a year later.

[20] After his freshman year, 19-year-old Glass looked around Baltimore for work in television, radio, and advertising without success;[9][10] meanwhile, he was employed in the shock trauma unit at a medical center.

[18] After someone at the local rock station recommended that he seek out Jay Kernis at National Public Radio's headquarters in Washington, DC,[10] he found work as an unpaid intern editing promotional announcements, before becoming the production assistant to Keith Talbot.

[18] When he graduated from college, they placed a sardonic ad in the classified section of their local newspaper that read, "Corporate office seeks semiotics grad for high paying position.

"[25] He has also said that editing for Noah Adams, an early host of All Things Considered, taught him how "to step back from the action and move to some bigger thought and then return to the plot", a technique that he still uses to structure This American Life.

[10] As he approached 30, he tried reporting his own stories, but said he was not good at it and that he performed poorly on air, took a long time to create a single piece, and did not have strong interviewing skills.

[29] Soon, he and Gary Covino created and co-hosted a Friday-night WBEZ Chicago Public Radio program called The Wild Room, which featured eclectic content with a loose style and aired for the first time in November 1990.

[30] In Glass's first professional interview (with Cara Jepsen in 1993), he said: "I like to think of it as the only show on public radio other than Car Talk that both NPR news analyst Daniel Schorr and Kurt Cobain could listen to.

[32] Glass eventually tired of "free-form radio" and, looking at other opportunities, began sending grant proposals to the Corporation for Public Broadcasting.

[3] Malatia approached Glass with the idea, who countered that he wanted to do a weekly program, but with a different premise, a budget of US$300,000, and a desire to make it a national show.

[6] It included interviews with talk-show host Joe Franklin and Shirley Glass—who maintained her position that her son should consider work in television because of his resemblance to Hugh Grant—as well as stories by Kevin Kelly (the founding editor of Wired) and performance artist Lawrence Steger.

[6] The show's name changed to This American Life beginning with the episode on March 21, 1996,[35] and was syndicated nationally in June 1996 by Public Radio International after NPR passed on it.

[36] Glass devoted himself to the effort by making the daily commute from his North Side apartment and spending 70 to 80 hours per week in the offices on the Navy Pier.

[33] Over the years, guest contributors included Dave Eggers, Sarah Vowell, Michael Chabon, Tobias Wolff, Anne Lamott and Spalding Gray.

[37][3] Glass had to move to New York for filming,[33] and said in an interview with Patt Morrison on Southern California Public Radio that he lost 30 pounds (14 kg) over the project.

[37] In 2006, he was an executive producer of the feature film Unaccompanied Minors, which is based on the true story of what happened to This American Life contributing editor Susan Burton and her sister Betsy at an airport one day before Christmas.

[citation needed] Glass was credited as a co-producer in Birbiglia's 2016 film Don't Think Twice, alongside Miranda Bailey and Amanda Marshall.

[49] Users in the American market could click on a candy heart that corresponded to each letter in "Google" and listen to a different story of unusual love in the same style as the radio program.

[49] Roger Neill composed the music, while Glass, fellow American Life producer Miki Meek, and Birbiglia conducted the interviews.

[54][55] In 2004, UCLA commissioned a one-night storytelling event called Visible and Invisible Drawings: An Evening With Chris Ware and Ira Glass.

[56] In February 2005, Glass visited the Orpheum Theater in New Orleans to present Lies and Sissies and Fiascoes, Oh, My!, which shares a name with a This American Life compilation album.

[70] Glass also lent his voice to The Simpsons in Season 22 in the episode "Elementary School Musical" and appeared in a green motion capture suit in a John Hodgman segment on The Daily Show with Jon Stewart on November 4, 2010, where he acted as the main character of the Grand Theft Auto: Vice City video game.

Steve Johnson with the Chicago Tribune called Glass "the deliberately mysterious, apparently highly romantic force who is the program's host, co-founder and executive producer".

[28] After remarking that, unlike on most shows, Glass serves as the director, senior producer, host, administrator, librarian, and researcher, Chicago writer Sarah Vowell said, "Part of that is that he's a control freak.

"[9] American Journalism Review called his voice "adenoidal" and said it has a "slight stutter, not a speech defect, but a verbal tic, a device".

"[81] They shared a pit bull named Piney, which they refused to put down even after it bit several people including two children, drawing blood.

[37] His favorite podcasts include WTF with Marc Maron,[citation needed] The Daily,[92] Reply All, Radiolab, Heavyweight, Stay Tuned with Preet'.

[99][100] He was on the team that won the Gold Award for best documentary from the Third Coast International Audio Festival in 2013 for Harper High School,[101] and was inducted into the National Radio Hall of Fame in November 2014.

In 2020, Glass and the rest of the This American Life staff (together with Molly O'Toole of the Los Angeles Times and Emily Green of Vice News) won the inaugural Pulitzer Prize for Audio Reporting for the episode "The Out Crowd," which demonstrated "revelatory, intimate journalism that illuminates the personal impact of the Trump Administration's "Remain in Mexico" policy".