Kieth first came to prominence in 1984 as the inker of Matt Wagner's Mage, his brushwork adding fluidity and texture to the broad strokes of Wagner's early work at Comico Comics. In 1989, he drew the first five issues of writer Neil Gaiman's celebrated series The Sandman, but felt his style was unsuited to the book (specifically saying that he "felt like Jimi Hendrix in The Beatles") and left, handing over to his former inker Mike Dringenberg.
He acted as illustrator on two volumes of writer William Messner-Loebs' Epicurus the Sage and drew an Aliens miniseries for Dark Horse Comics, among other things, before creating The Maxx in 1993 for Image Comics, with, initially, writing help from Messner-Loebs. It ran for 35 issues and was adapted, with Kieth's assistance, into an animated series for MTV. Since then, as a writer-artist, he has gone on to create Friends of Maxx, Zero Girl, Four Women and Ojo.
Ojo comprises the first and My Inner Bimbo the second, in a cycle of original comic book limited series published by Oni Press. Loosely connected, the cycle will concern the intertwined lives of people with each other and sometimes with a supernatural entity known as the Mysterious Trout. Kieth has stated that other characters from The Maxx series will appear in this cycle of stories. My Inner Bimbo #1 was published in April 2006. Issue #2 was delayed past its original release date; It was finally resolicited in "Previews" in 2007 and hit the store shelves in November 2007.
DC Comics' Batman/Lobo: Deadly Serious, a two-issue prestige format mini-series that started in August 2007, was written and drawn by Kieth. This was followed by 2009's two-issue prestige format mini-series Lobo: Highway to Hell, written by Scott Ian and featuring art by Kieth.