Cloonan created minicomics and was part of the Meathaus collective before collaborating with Brian Wood on Channel Zero: Jennie One in 2003. Since then, her profile (and workload) has steadily risen; her best-known work to date has been the twelve-issue comics series Demo (2004), also with Wood. Wizard named Demo its 2004 "Indie of the Year." The series was also nominated for two Eisner Awards in 2005, for Best Limited Series and Best Single Issue (for #7, "One Shot, Don't Miss").

Cloonan's first solo graphic novel, East Coast Rising Volume 1, was released by Tokyopop in 2006. East Coast Rising: Volume 1 marked Cloonan's third Eisner Award nomination in 2007, this time for Best New Series. She also collaborated with writer Steven T. Seagle on the Vertigo Comics series American Virgin, which was cancelled with the 23rd issue.

Cloonan is currently finishing East Coast Rising Volume 2, and working again with Brian Wood on 6 new issues of DEMO to be published by Vertigo.

She has also created artwork for the band Leftover Crack and hip-hop group CunninLynguists.

Comics work includes:

• Demo (with Brian Wood, 12-issue limited series, AiT/Planet Lar, 2003—2004)
• Bram Stoker's Dracula: The Graphic Novel with Gary Reed (Puffin Books, 2006, ISBN 0-14-240572-8)
• East Coast Rising (Tokyopop, 2006, ISBN 1-59816-468-6)
• American Virgin #1-17, 20-23 (pencils, with Steven T. Seagle, Vertigo, 2006—2008)

Other works:

• "MINIS" - collection of original mini-comics, re-issued in one volume (2007, self-published)
• Bury Your Treasure - collection of illustrations in black-and-white (2009, self-published)