Reis became involved in music in 1984, playing in a punk rock band called Conservative Itch at age 15. In 1986 he formed the post-hardcore group Pitchfork with friend Rick Froberg, in which he played until the group's dissolution in 1990. Following this he formed two new bands: Drive Like Jehu included Froberg and was the more experimental, exploring styles such as post-punk, post-hardcore, math rock, and early-1990s emo. Rocket from the Crypt, meanwhile, was envisioned as a more back-to-basics rock band and involved other San Diego-area musicians. Both groups released debut albums in 1991 through local labels Cargo Records and Headhunter Records. Rocket from the Crypt was soon re-invented as a punk-inspired rock & roll band with a horn section, developing a reputation for creative and energetic live shows. The group released many vinyl singles and put out their second album Circa: Now! in 1992. Reis' heavy involvement with Rocket from the Crypt sidelined Drive Like Jehu at this time, but both groups were soon signed to major label Interscope Records as a pair.

In 1994 Rocket from the Crypt took a six-month break while Reis returned to work with Drive Like Jehu, recording the critically acclaimed album Yank Crime. At this time he also recorded an album's worth of solo material under the project name Back Off Cupids, but the majority of this work went unreleased until 1999. In 1995, with little fanfare, Drive Like Jehu disbanded and Reis resumed working with Rocket from the Crypt full time. The group experienced a flurry of creativity that resulted in a trilogy of releases that year, culminating in the acclaimed album Scream, Dracula, Scream! They became well known in the alternative music community, filmed several music videos, toured internationally, and experienced a surge of popularity in the United Kingdom. They released a follow-up entitled RFTC in 1998, but Interscope turned their attention to higher-grossing acts and soon the band left the label. This was followed by the departure of longtime drummer Adam Willard from the group in early 2000, resulting in a hiatus of sorts during which Reis explored other musical endeavors.

In 1999 Reis started the record label Swami Records, primarily as a means of releasing music by a number of San Diego-area bands including several he was involved with. He also formed two new bands: Sessions with drummer Jason Kourkounis resulted in the formation of Hot Snakes (which also reunited Reis with Rick Froberg), while collaborations with drummer Tony Di Prima led to the formation of the Sultans. Both bands essentially explored stripped-down versions of the musical formulas Reis had established in Rocket from the Crypt, with Hot Snakes incorporating some of the more experimental elements of Drive Like Jehu while the Sultans used a more straightforward rock & roll approach. During this time Reis recorded and acted as producer for a number of groups, including Superchunk, Selby Tigers, GoGoGo Airheart, and the Red Onions. He also performed on and off with other bands including Stacatto Reads, Custom Floor, and Beehive and the Barracudas.

Rocket from the Crypt regrouped in 2000, signing to Vagrant Records and bringing in new drummer Mario Rubalcaba. Reis continued to record and perform with Rocket from the Crypt, Hot Snakes, and the Sultans for the next several years, dividing his time between all three groups. Between 1999 and 2005 he recorded 2 albums with Rocket from the Crypt, 2 with the Sultans, and 3 with Hot Snakes. In 2003 his younger brother Dean Reis joined him in the Sultans. Rubalcaba also became a member of all three of Reis' bands, replacing Kourkounis in Hot Snakes in 2004 and Di Prima in the Sultans in 2006.

2005 marked the end of Reis' multi-band involvement, with the breakups of Hot Snakes in July and Rocket from the Crypt on Halloween. He then focused his attention on Swami Records, putting out numerous releases that Fall and Winter and organizing tours in support of the label. He began hosting the "Swami Sound System" program on San Diego radio station 94.9 (KBZT) and continued to play with the Sultans occasionally until their disbanding in January 2007.

Reis continues to operate Swami Records and acts as a producer and occasional studio musician for various artists and releases on the label, while focusing on his new role as a father. He constructed his own recording studio and opened a bar called The Bar Pink Elephant (later renamed Bar Pink) in San Diego's North Park district. In 2007 he announced a new musical project, and began recording and writing new songs with former Hot Snakes members Gar Wood and Jason Kourkounis and CPC Gangbangs bassist Tommy Kitsos. Reis described the new group as "a combonation [sic] of everything I've been a part of dating back to my prepubescent days in Pitchfork. Similar to Hot Snakes but not as sinister yet still maintaining some of the drama and subsonic boom. Akin to the rockin' fun of RFTC but without the same kind of riffery. Like the Sultans but not as straightforward yet still maintaining the sense of melody and pop of the 2nd record."^[3][4][5][6] Dubbed the Night Marchers, the new group began performing and touring in 2008 with Reis again using the stage name "Speedo". Their debut album See You in Magic was released on April 22, 2008.

Reis continues to host the "Swami Sound System" program on San Diego radio station 94.9 on Saturday nights and is preparing several releases of rare and previously unreleased Rocket from the Crypt material.^[3] He also plays a recurring role on the television show Yo Gabba Gabba as the Music Swami, introducing each episode's musical guest.

In 2011 Hot Snakes announced they will be reforming for tours the US and Europe.^[7]

In 2015, Reis produced American rock band Ceremony's fifth studio album, The L-Shaped Man.^[8]

In March 2015, Vintage Piss was released by Sonny Vincent and Rocket from the Crypt. The album was originally recorded with Vincent in 2003 following a tour with Rocket from the Crypt serving as his backing band however the album was left unmixed and unfinished until twelve years later following the reunion of Rocket from the Crypt when Reis decided to go back and complete the album, which he also produced.^[9]

On 9/8/21 he made his debut with Me First and the Gimme Gimmes at Express Live! in Columbus, OH performing with CJ Ramone, Andrew "Pinch" Pinching, Jonny "2 Bags" Wickersham and Spike Slawson.

Reis is married. He and his wife had their first child in 2006.^[10]

Many artists have cited John Reis as an influence or have expressed admiration for his work, including Jim Adkins of Jimmy Eat World,^[11] Kurt Ballou of Converge,^[12] Laurent Barnard of Gallows^[13] and Steven Andrew Miller of Unbroken.^[14] According to Doug McCombs of Tortoise-fame:^[15]

John Reis fills a void. It's a cynical world and there aren't many true believers in rock & roll anymore. He's the carnival barker that lures you into rock & roll. He believes in rock & roll wholeheartedly and wants you to believe too. He's a genius at guitar riffs. He's evidence that rock & roll is not played out.

This section lists albums and EPs on which Reis has performed. For complete listings of releases by each act, see their individual articles.

• Hot Snakes official website
• Rocket from the Crypt official website
• John Reis discography at Discogs