She started her career with "Stay (I Missed You)" from the film Reality Bites, the first Billboard number one single for an artist without a recording contract.

Her mother, Gail, was the president of the Dallas County Medical Society Alliance and Foundation, and her father, Peter Loeb, was a gastroenterologist.

[14] At Brown in the mid-1980s, Loeb and Elizabeth Mitchell formed a band named Liz and Lisa,[14] with future singer/songwriter and classmate Duncan Sheik as a guitarist.

Loeb attended Berklee College of Music in Boston for a session of summer school, and in 1990 formed a full band called Nine Stories.

[19] Loeb and Nine Stories received a Grammy nomination for Best Pop Performance by a Group, and were named Best International Newcomer in the Brit Awards.

[19] Critics were favorable to the album, with Ken Tucker of Entertainment Weekly, in particular, noting, "Loeb has an undeniable gift for creating an air of intimacy and vulnerability, which may well be enough for 'Stay' fans looking for additional doses of contemplative melancholy".

[citation needed] Firecracker included hit singles such as "I Do", which received radio success, peaking at #17 on the Billboard Hot 100 and music television.

[2] In 2000, Loeb participated in the Ozzy Osbourne tribute album Bat Head Soup, performing "Goodbye to Romance" with Dweezil Zappa on guitar.

Other international work includes Loeb's guest performance on the song "Anti-Hero" for an all-female Japanese musical group Rin''s album Inland Sea.

[23] Loeb contributed vocals to New Found Glory's cover of "Stay", from their 2007 LP From the Screen to Your Stereo Part II, as well as performing the song live with the band.

She co-produced the album and collaborated with Glen Ballard, then boyfriend Dweezil Zappa, Randy Scruggs (Vince Gill, Sawyer Brown, Waylon Jennings), and Peter Collins (Rush, Bon Jovi, Indigo Girls).

Loeb toured the world again, making special stops in Sanrio stores for in-store autographs while appearing with Hello Kitty at the Japanese MTV Music Awards.

In 2003, Loeb reunited with her college music partner Elizabeth Mitchell on children's CD and companion book Catch the Moon through Artemis Records.

[28] Stephen Erlewine called it "the best, most cohesive record she's made, a clean, crisp collection of well-crafted, gentle tunes that slowly, surely work into the subconscious.

[29] In 2006, Loeb contributed to the album A World of Happiness, designed to disseminate messages of kindness, compassion, tolerance, and self-reliance to children of all ages.

[38] The Hanukkah song tells a "story of hope in the darkness", and was co-written by Loeb and Cliff Goldmacher, with Renee Stahl on guest vocals.

The show received a positive write-up in The New York Times, with the review describing it as "fresh and funny" and praising the acoustic music and characterizations of the campers.

The album features Lisa and Larry's arrangements of classic songs like Dionne Warwick's "What the World Needs Now Is Love", the Five Stairsteps' "O-o-h Child", and Fleetwood Mac's "Don't Stop.

[citation needed] On May 29, 2019, Rolling Stone premiered Loeb's studio-recorded cover of the Bright Eyes song "First Day Of My Life."

[60] In October 2019, Loeb preceded the album's release with the premiere of her single "Sing Out" on the largest LGBTQ news site Queerty, in honor of National Coming Out Day.

She has subsequently released music videos for many of the tracks on the album, including "This Is My Life", "Another Day", "Sing Out', "For the Birch", "Shine", "The Upside", "Doesn't It Feel Good", "Most of All", "I Wanna Go First" and "Wonder".

[citation needed] In August 2021, Loeb saw the premiere of Together Apart, a musical consisting of a collection of 10 seven-minute-long mini-musicals all about connecting on Zoom at the beginning of the COVID-19 pandemic.

[63] In 1989, Loeb appeared in the low-budget comedy horror anthology film Tabloid, in a segment entitled "Killer Vacuum Destroys Town".

[4] In the fall and winter of 2005, following her breakup with Zappa,[5] Loeb taped a reality show called Number 1 Single,[2] which premiered in January 2006 on the E!

[65] In September 1999, she made an appearance on the comedy show MADtv, singing the theme song for a WB drama sketch called "Pretty White Kids with Problems".

[67] In 2008, she made a guest appearance on Gossip Girl,[13] followed by a cameo on an episode of The Sarah Silverman Program in which the cast formed a mock band called "The Loeb Trotters".

On the final episode of Gossip Girl on Monday, December 17, 2012, Lisa ended up with the character Rufus Humphrey in the five years after glimpse.

In addition to television shows, Loeb has also appeared in the horror films House on Haunted Hill (1999), Serial Killing 4 Dummys (1999), and Fright Night (2011).

[73] In April 2014, Loeb appeared in the first episode of Last Week Tonight with John Oliver in a short musical sketch about Oregon's health care website failure.

[74] In 2015, Loeb appeared as Julie, lead singer of the fictitious band "Natalie is Freezing", in the episode "Advanced Safety Features" of the TV series Community.