In 1973, Vai began to take guitar lessons from fellow New York native Joe Satriani, and played in local bands (The Ohio Express, Circus, and Rayge) throughout his high school years.

[23][24] Impressed by this, Zappa responded by putting Vai on salary to transcribe his work, which included pieces from the Joe's Garage and Shut Up 'n Play Yer Guitar albums.

In 1985, Vai joined David Lee Roth's post-Van Halen band as lead guitarist, together with former Talas bassist Billy Sheehan on bass; and former Maynard Ferguson drummer Gregg Bissonette on drums.

[40] Upon its release in November 1989, Slip of the Tongue sold over three million copies worldwide, reaching number 10 on the Billboard 200 while Vai joined the band on their thirteen-month world tour.

Vai left Whitesnake in 1990 to pursue his own musical avenues and formed a band that included Devin Townsend on vocals, T. M. Stevens on bass, and Terry Bozzio on drums.

[45] The group released Sex & Religion on July 23, 1993, that was described as visceral in nature, combining a compositional and progressive metal rhythm section with Devin Townsend's vocal arrangements.

[59] In December 2001, Vai recorded two performances at The Astoria in London, with his band The Breed (composed of former David Lee Roth bandmate Billy Sheehan, guitarist/pianist Tony MacAlpine, guitarist Dave Weiner, and drummer Virgil Donati).

[63] Having always enjoyed the aspect of teaching and sharing his experiences in life and in the music business,[citation needed] Vai began a series of "Alien Guitar Secrets" masterclasses in 2006- a touring masterclass in which Vai holds open forum discussion about his own experiences in the music industry, explains the key principles to understanding success, plays to backing tracks (often inviting class attendees to jam with him), answers questions, articulates key points of guitar technique, and more importantly goes beyond the technique and into the more profound esoteric principles at play (see Notable contributions for more on this).

I & II and Visual Sound Theories, Vai put together a new band for a five-month world tour of the United States, Europe, South America, and Australia.

Midway through the String Theories tour in 2007, Vai recorded a performance at the State Theatre in Minneapolis, which yielded the acclaimed 2009 live concert DVD and Blu-ray release of Where the Wild Things Are.

Certified gold in the United States and Canada, Where the Wild Things Are showcased the diverse musical range of the String Theories band, with pieces such as the visceral Grammy-nominated "Now We Run", to the dynamic ballad "Angel Food".

[77] In April, Vai performed with Mary J. Blige, Orianthi, Randy Jackson, and Travis Barker for a rendition of the Led Zeppelin classic "Stairway to Heaven", on the hit television show American Idol.

[82] In April 2011, Vai (along with music and technology entrepreneur Andy Alt) announced the launch of GuitarTV, an online streaming website dedicated to bringing free guitar-related content to the community of guitar players around the world.

Released on April 7, the double-disc set contained a copy of the Stillness in Motion concert footage and a special bonus feature disc called The Space Between the Notes.

During the day, Vai and the special guests (some of whom have been Guthrie Govan, Jeff Baxter, Vernon Reid, Eric Johnson, Sonny Landreth, and others) hold classes in which they add their insight and perspective to the theme.

Next year, double disc DVD “Stillness in Motion: Vai Live in L.A.Stillness In Motion" was released with a bonus disc premiering “The Space Between the Notes", a revelatory video diary consisting of more than three and a half hours of footage, lensed around the world on-stage, off-stage and behind-the-scenes, rehearsal and the show moments of Steve's joint performance with Roman Miroshnichenko and orchestra during Vai’s "Story of Light" World Tour.

In April and May of the same year, Vai took part in the Generation Axe tour, alongside Tosin Abasi, Nuno Bettencourt, Yngwie Malmsteen, and Zakk Wylde.

Having previously covered her composition, "Mullach a tSí" for The Story of Light in 2012 and performing together in Vicar Street in Dublin, Vai collaborated with Pádraigín Ní Uallacháin for the title track of her 2023 album, Seven Daughters of the Sea.

[97] In September 2024, Vai joined Adrian Belew, Tony Levin and Tool drummer Danny Carey on a three-month tour of North America called "Beat".

The video covers his life growing up, attending Berklee College of Music, playing with several artists like Frank Zappa, Alcatrazz, the David Lee Roth band, and Whitesnake, the recording of both his solo albums Flex-Able and Passion and Warfare, plus Vai's role in the movie Crossroads, and how he helped create the Ibanez JEM guitar.

David Lee Roth's "Yankee Rose" was featured on Vice City's soundtrack, as well as "God Blessed Video" by Alcatrazz, as part of the Lazlow-led, 1980s rock/metal radio station "V-Rock."

A live version of "For the Love of God" was also available on the Rock Band Network service, as well as the song "Get the Hell Out of Here" from his 2002 compilation album The Elusive Light and Sound Vol.

[101] The main body of the final piece performed in the duel scene (the fast-paced neoclassical track "Eugene's Trick Bag") was based heavily on Niccolò Paganini's Capriccio number 5.

[86] In speaking of his inspiration, Vai has said that it comes to him in many forms (even from the flowers pushed up against a fence outside of his studio, which he transcribed and used in the ninth track "Weeping China Doll", from The Story of Light.

[112][113] Vai cites artists such as Jimmy Page, Brian May, Ritchie Blackmore, Jeff Beck, Jimi Hendrix, as well as jazz fusion guitarists Allan Holdsworth and Al Di Meola as some of his major influences.

The Universe incorporated many of the aspects that made the JEM a unique instrument (2 octave fretboard, full floating tremolo, humbucker/single coil/humbucker pickup configuration, angled output jack and deeper body cutaways), with an added low 'B' string, allowing for new low-range sonic possibilities.

Used by Vai on much of Passion and Warfare and all of Whitesnake's Slip of the Tongue, the Universe was a large stepping stone for the burgeoning Nu-metal genre (with bands such as Korn, Limp Bizkit, Fear Factory and Meshuggah having adopted the instrument and incorporating it into their signature sound).

[118] Having always enjoyed the aspect of teaching and sharing his experiences in life and in the music business, Vai began a series of "Alien Guitar Secrets" masterclasses in 2006- a touring masterclass in which Vai holds open forum discussion about his own experiences in the music industry, explains the key principles to understanding success, plays to backing tracks (often inviting class attendees to jam with him), answers questions, articulates key points of guitar technique, and more importantly goes beyond the technique and into the more profound esoteric principles at play.

[125] In the 1990s, Vai began touring in European and Asian countries (such as Russia and China) as well as South America, often having been the first American rock act in history to have performed in these areas.

[143] Vai's 2016 live guitar rig utilizes his signature Carvin Legacy amplifier (now on its third version), the Fractal Audio Axe-Fx II XL, and an MFC-101 foot controller.