From 1993, Pastis worked as a litigation attorney in the San Francisco Bay area. At this time he also tried to fulfill his childhood ambition of becoming a syndicated cartoonist by submitting various concepts to syndication agencies. The Infirm, Rat, and Bradbury Road  were rejected, but Pearls Before Swine was accepted by United Features in 1999. It started publication on December 31, 2001, and is still one of the fastest-growing comic strips, appearing in more than 450 newspapers worldwide and counting. Pastis left his law job in August 2002. His wife is named Staci.
The character of Rat came from Pastis's earlier strip, Rat. The character of Pig was based on pigs that had been featured in The Infirm. When Pastis invented the characters of Pig and Rat, they were just stick figures with jokes. One day when he was still a lawyer, he went to a cafe to try to meet Charles Schulz, creator of Peanuts. Schulz inspired him to go on from just sketches during lectures to full-fledged cartooning. He learned how to write by studying Dilbert comics in bookstores. He then collected the 40 comics that his attorney colleagues liked the best. Fearing another rejection, however, Pastis put them in an envelope and let it sit on the counter in his basement. It sat there for a year until he visited a friend's grave and, feeling as though he had let her down, had a change of heart. He sent it out six weeks later and with help from Scott Adams, United Features Syndicate called him to inform him that he was being considered for syndication. Pearls Before Swine was launched in syndication in 2001.
This information can be found in the introduction to Pastis's first treasury, Sgt. Piggy's Lonely Hearts Club Comic. In this treasury and the three that have followed (Lions and Tigers and Crocs, Oh My!, The Crass Menagerie and Pearls Sells Out) he includes background information on many of the strips they contain, as well as printing the Sunday strips in full color. In addition, the three treasuries following Sgt. Piggy's Lonely Hearts Club Comic have included a section following the collected strips where Pastis shows other strips that were either edited because of content or that he just pulled from papers for various reasons, with explanations as to why these strips didn't run.
Pastis works up to nine months ahead of deadline, a rarity in the world of newspaper comics.
Pastis was nominated for the National Cartoonists Society Newspaper Comic Strip Award for 2002, 2003, 2006, and 2007. He won the 2003 and 2007 awards.