In June 2012, Notaro did a Kickstarter-funded series called Clown Service written by her and starring herself. She worked on fellow comedian Amy Schumer's Comedy Central series Inside Amy Schumer. I love your voice." After her monologue, Dayne made a surprise appearance, serenading Notaro with the song "I'll Always Love You". She performed a monologue about having encountered Taylor Dayne on multiple occasions, greeting her each time with, "Excuse me, I'm sorry to bother you, but I just have to tell you. In 2012, Notaro appeared on Conan, and in May of that year on the live episode of This American Life, which was broadcast to theaters nationwide and on radio in edited form. Her 2012 album, Live, is a recording of a stand-up set performed shortly after she was diagnosed with breast cancer. In 2011, she released her debut stand-up album, Good One. With Dunnigan and David Huntsberger, she co-hosted the podcast Professor Blastoff from May 2011 until July 2015. She collaborates frequently with writing partner Kyle Dunnigan. Notaro has since been featured on Comedy Central Presents and on The Sarah Silverman Program as a lesbian police officer. Notaro's work promoting bands took her to Los Angeles, where she tried stand-up for the first time in the late '90s. She became a band manager, working under the name Tignation Promotions in the mid-'90s. Notaro moved to Denver, Colorado, where she became involved in the music industry. In 1990, while living in Texas, Notaro got her general equivalency diploma. Notaro failed three grades, eventually dropping out of high school. In an interview with magazine Mother Jones, she said she disliked school. When taking part in season 5 of Finding Your Roots with Henry Louis Gates, Jr., Notaro found out that she is also a distant cousin of Gloria Steinem. Notaro's maternal great-great-grandfather was John Fitzpatrick, mayor of New Orleans from 1892 to 1896. She has a brother, Renaud Notaro, who is a year her elder and works as a radio talk show host. Her family later moved to Spring, Texas, a suburb of Houston.
Notaro was raised in Pass Christian, Mississippi, until kindergarten. Notaro was born in Jackson, Mississippi, the daughter of Mathilde “Susie” O'Callaghan and Pat Notaro.