He began his musical career by playing for ‘Panic’; a band member and the sound man were killed in a car crash after the band’s first show.
In 1981, he joined ‘Metallica’ as the band’s lead guitarist. He toured with them and wrote/co-wrote several songs, including, ‘Kill Em All’ and ‘Ride the Lightning’. He was officially fired from the band two years later.
After moving to California, he secured his first real job as a telemarketer. He quit it after he had made enough money to move to an apartment in Hollywood and started the short-lived band, ‘Fallen Angels’.
He formed the band ‘Megadeth’ (based on the name of a song he wrote) with Dave Ellefson and Greg Handenvidt who lived in the apartment below his. 'Lor' Kane lent his voice for a short time as the lead vocal but Mustaine chose to be the lead vocal himself.
In 1984, Megadeth cut a three-song demo and later that year, the band signed a deal with ‘Combat Records’ and began touring.
In May 1985, Megadeth released their debut album, ‘Killing Is My Business... and Business Is Good!’ and toured the US and Canada.
In 1986, the band released the landmark album, ‘Peace Sells... but Who’s Buying?’. The title track and ‘Wake up Dead’ became huge hits. A year later, they embarked on their first world tour, which began in the U.K.
Megadeth released their third album, ‘So Far, So Good... So What!’ in 1988, which featured hits like ‘In My Darkest Hour’, ‘Hook in Mouth’, and ‘Anarchy in the UK’. Later that year, Mustaine produced the album, ‘Refuge Denied’ for the band, ‘Sanctuary’.
In the 90s, they released a number of albums including; ‘Rust in Peace’, ‘Countdown to Extinction’, ‘Youthanasia’, and ‘Cryptic Writings’, which tasted continued commercial success.
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In addition, Mustaine covered the 1992 Democratic National Convention for MTV, worked on the Clash of the Titans Tour, closed the Woodstock '99 music festival, and fired Marty Friedman from the band.
They began the new millennium with ‘Capitol Punishment: The Megadeth Years’, a ‘best of’ collection, produced by Capitol Records.
In 2002, Mustaine disbanded Megadeth after he suffered a freak injury which left him unable to grasp or even make a fist with his left hand. During the period of recuperation, he converted to Christianity.
After a surprisingly quick recovery, he oversaw the remixing and re-mastering of Megadeth’s entire Capitol Records catalog and released ‘The System Has Failed’, in 2004.
In the second half of the decade, he created Gigantour with the band, ‘Dream Theater’, ‘Arsenal of Megadeth’ (a two-disc anthology DVD) and recorded the albums, ‘United Abominations’ and ‘Endgame’.
In 2010, Megadeth embarked on a ‘Rust In Peace’ 20th Anniversary tour, played with The Big Four (Metallica, Slayer, Megadeth, and Anthrax)m and released his autobiography, ‘Mustaine: A Heavy Metal Memoir’.
In 2011, Mustaine played five songs with Metallica at the Fillmore Theater as a part of the band's 30 year anniversary celebration.