Frank Gambale was born on December 22, 1958, in Canberra, Australia, into a family of musicians. According to his own biography, he grew up on the blues and rock guitar of the 1960s and 1970s, was drawn as a teenager toward jazz and vocal-based music, took up piano at 17 and nearly gave up the guitar, then went back to it about two years later at the urging of his older brother. In the early 1980s he moved to Los Angeles to be where the music he loved was being made, enrolled at the Guitar Institute of Technology in Hollywood, graduated as Student of the Year, and taught there from 1984 to 1986. His book Speed Picking (1985) and the video Monster Licks & Speed Picking (1988) set out the sweep-picking and economy-picking methods that became his signature.

His first records came out on Legato, with Mark Varney as executive producer: Brave New Guitar (1986), with pianist Kei Akagi among the players, and A Present for the Future (1987), whose guests included bassist John Patitucci, drummer Steve Smith, and keyboardist Tom Coster, and which contains a piece titled "Legends (Dedicated to Chick Corea)." His official biography says he toured with Jean-Luc Ponty in the summer of 1986 and was invited to join Chick Corea's Elektric Band afterward. On Light Years (GRP, 1987) he replaced Scott Henderson as the band's full-time guitarist, playing on six of the album's twelve tracks alongside saxophonist Eric Marienthal, Patitucci, and drummer Dave Weckl; the album received the 1988 Grammy for Best R&B Instrumental Performance. He stayed through Eye of the Beholder (1988), Inside Out (1990), and Beneath the Mask (1991), a stretch Wikipedia puts at six years and two Grammy nominations. For the 1993 album Elektric Band II: Paint the World, only Corea and Marienthal returned from the earlier lineup. Gambale came back for the 1996 tribute album The Songs of West Side Story, rejoined the Elektric Band in the early 2000s, and appears on To the Stars (Stretch, 2004) and the Live at Montreux 2004 video; his official site describes a 2017 world tour by the same five players.

Away from Corea he built his own catalogue and joined several bands. On JVC he made Thunder from Down Under (1990), Note Worker (1991), The Great Explorers (1993), Passages (1994), and Thinking Out Loud (1995). With the Mark Varney Project, which Wikipedia describes as also including Allan Holdsworth, Brett Garsed, and Shawn Lane, he recorded Truth in Shredding (Legato, 1990) and Centrifugal Funk (1991). He guested on four tracks of Steve Smith's Vital Information album Fiafiaga (1988), was the band's guitarist on Vitalive! (1990), and stayed for twelve years, through Easier Done Than Said (1992), Ray of Hope (1996), Where We Come From (1998), Live Around the World (2000), Show 'Em Where You Live (2001), and Come On In (2004). With bassist Stuart Hamm and Smith he formed the trio GHS, which made Show Me What You Can Do... (Tone Center, 1998), The Light Beyond (2000), and GHS3 (2002).

His later leader work moved between acoustic and electric settings and several labels. Coming to Your Senses (Favored Nations, 2000) was followed by Raison d'Être (ESC, 2004) with drummer Billy Cobham. On Wombat Records he issued the acoustic Natural High (2006), with bassist Alain Caron and pianist Otmaro Ruiz, then Natural Selection (2010), the vocal collaboration Soulmine (2012) with the singer Boca, and Salve (2018) under the name Frank Gambale Soulmine. In Italy he recorded Imagery Suite (1999) and a live album with classical guitarist Maurizio Colonna, and with drummer Virgil Donati and six-string bassist Ric Fierabracci he made Made in Australia (2007). In 2011 he rejoined Corea in Return to Forever IV, the reunion lineup with Stanley Clarke, Ponty, and Lenny White, which his official biography says played more than 100 concerts and which produced the live set The Mothership Returns (2012).

Gambale has also been a teacher. Wikipedia lists him as former head of the guitar department at the Los Angeles Music Academy, and he took the same role with the Isina mentorship program in 2014. His online school, the Frank Gambale Guitar School, opened in 2015 and has since been relaunched on a new platform, and his official site lists concerts under the name FG All Stars and masterclasses in Europe.

Gambale is identified with sweep picking, in which one pick stroke sweeps across adjacent strings to play an arpeggio at speed, and with economy picking, techniques whose appeal for him lay in moving past the physical limits of the guitar and borrowing from piano and saxophone. In his own words he does not want to be boxed in as only a fusion guitarist, and his catalogue bears that out: AllMusic files him under Fusion and Guitar Jazz, and his records range from acoustic playing to funk, rock-edged fusion, and smooth jazz. He also devised the Gambale Tuning, in which the guitar is tuned up a fourth and its top two strings are dropped an octave (A, D, G, C, E, A, low to high), a layout that lets him voice chords close together the way a keyboard player does. Among those who have cited him as an influence are Synyster Gates, Dweezil Zappa, Greg Howe, and Pat Metheny, and in a 1991 Rolling Stone interview Jerry Garcia named him a current favorite. Scott Yanow wrote the AllMusic biography and includes him in The Great Jazz Guitarists, and the New Grove Dictionary of Jazz has an entry on him.