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Formed in 1983 by guitarist/vocalist Dave Mustaine and bassist David Ellefson, Megadeth became one of the most acclaimed and successful thrash metal outfits of their era and beyond. Part of the "big four" of the genre along with Metallica, Anthrax, and Slayer, the group expanded on the typical metal blueprint by speeding up the tempos and putting an emphasis on lightning-fast technical guitar skills. Mustaine's nihilistic lyrics and the band's unrelenting musical attack resulted in a series of early thrash classics. 1986's Peace Sells... But Who's Buying? and 1992's Countdown to Extinction sold in the millions and influenced the next generation of speed metal bands, while later efforts like 2007's United Abominations, 2016's Grammy-winning Dystopia, and 2022 album The Sick, The Dying... And the Dead! revealed a band with plenty of gas left in the tank.

Throughout Megadeth's many lineup changes, the two core members were bassist Dave Ellefson and guitarist/vocalist Dave Mustaine (born September 13, 1961), who was the band's official leader. Mustaine grew up in the suburbs of Southern California, where he was raised by his mother in a broken home; his mother often left him to be raised by aunts and uncles, who never encouraged his musical inclinations and often belittled him for his fondness for heavy metal. In 1981, he formed Metallica with James Hetfield and Lars Ulrich. Mustaine spent two years with Metallica, developing a strong cult following in California's underground metal scene, before he was kicked out of the group in 1983, allegedly over his substance abuse. Immediately following his firing, he formed Megadeth with Ellefson, Slayer guitarist Kerry King, and drummer Lee Rauch. This lineup was extremely short-lived, and Mustaine and Ellefson soon recruited guitarist Chris Poland and drummer Gar Samuelson.

For the next few years, Megadeth toured and gained a following, signing with the independent label Combat in late 1984. The following year, the group released its debut, Killing Is My Business...And Business Is Good!, which received strong reviews, not only in metal-oriented publications, but also in mainstream music magazines. The album sold very well for an independent release, which attracted the attention of major record labels. By the end of the year, the group had signed with Capitol. Megadeth's first major-label album, Peace Sells...But Who's Buying?, was released in the fall of 1986. Like its predecessor, Peace Sells was greeted by strong reviews and sales and eventually went platinum.

Although the band's fortunes were on the upswing, Mustaine was beginning to sink deeper into drug abuse, specifically heroin. Soon, his addictions began to affect his work. Many stories concerning his erratic behavior were circulating within the metal community, and they seemed to be proven correct when he fired both Poland and Samuelson before the recording of the band's third album; they were replaced by Jeff Young and Chuck Behler, respectively. The new lineup debuted on So Far, So Good...So What!, released early in 1988. So Far, So Good peaked at number 28 on the charts and also eventually went platinum (despite less-than-enthusiastic reviews); it also featured a notorious cover of the Sex Pistols' "Anarchy in the UK" with incorrect lyrics.

In the years immediately following the release of So Far, So Good...So What!, Mustaine was impaired by his drug addictions. In early 1990, he was arrested for driving under the influence and entered a rehabilitation program. By the end of the year, he was not only sober but had reconvened the band, firing Young and Behler and replacing them with guitarist Marty Friedman and drummer Nick Menza. This lineup recorded Megadeth's fourth and most progressive album, Rust in Peace. The record peaked at number 23 on the American charts and went platinum. Metallica broke through to the mainstream in 1991, and sensing the possibility for similar success, Mustaine followed suit in stripping down Megadeth's sound, though it remained as technically perfectionist as Rust in Peace. The result, Countdown to Extinction, was released in 1992, entering the charts at number two; the record went double platinum and became the band's biggest hit, confirming that they had retained their audience in the wake of grunge.

Now one of the most popular metal bands in the world, Megadeth moved further toward the mainstream with Youthanasia in 1994, which entered the charts at number four and, like its predecessor, went platinum. The following year, the group released Hidden Treasures, a rarities collection that featured some of the soundtrack tunes that had helped expand the group's MTV audience in the early '90s. Released in 1997, Cryptic Writings found Megadeth fully embraced by album rock radio, which formerly would never have touched the band. Ex-Suicidal Tendencies drummer Jimmy DeGrasso signed on in 1998, in time for the following year's Risk. In 2000, following the release of the best-of Capitol Punishment, Marty Friedman followed Nick Menza out the door; he was replaced by former Savatage and Alice Cooper guitarist Al Pitrelli. After signing with the BMG subsidiary Sanctuary, Megadeth debuted their new lineup on 2001's The World Needs a Hero.

While on break from touring, Mustaine suffered a serious injury in January 2002 while staying in Texas. He was diagnosed with having radial neuropathy shortly thereafter, a condition that prevented him from playing guitar. The compressed radial nerves in his left arm and hand were strained, leaving Megadeth little recourse but to disband in April 2002 after almost 20 years in the music industry. During his time off, Mustaine prepared an elaborate reissue campaign, remastering each album and reissuing them all with bonus material. This campaign set the stage for a Megadeth revival, which came in 2004 and 2005 with a surprising comeback album, The System Has Failed, and some heavy touring. Capitol released a new best-of, simply titled Greatest Hits, just as Megadeth hit the summer concert circuit, headlining Mustaine's own Gigantour Festival. In 2007, Megadeth released the politically charged United Abominations, followed by the similarly apocalyptic Endgame in 2009. Released in 2011, Th1rt3en was the first Megadeth album since 2001's The World Needs a Hero to feature the bass playing of founding member Dave Ellefson and production by Johnny K (Staind, Disturbed). Containing some of the band's darkest and heaviest material in years, it combined new songs with older ones written years ago but never recorded. In 2012, the band embarked on a tour playing its fifth album, Countdown to Extinction, in its entirety. The tour resulted in the release of concert album Countdown to Extinction: Live, which arrived the following year. Super Collider, the group's 14th studio outing, was also released in 2013. Just after its release, Mustaine and company pushed on, announcing on their website that Megadeth were already writing material for a follow-up album.

The band encountered a number of difficulties over the next two years. First, Mustaine's mother-in-law, who had been suffering from Alzheimer's disease, went missing in October of 2014; her body was discovered on a campground at the end of November. Ellefson's brother passed away after a struggle with cancer, and the band went on a brief hiatus to support him.

After hearing rumors that Mustaine was considering a reunion of the Rust in Peace lineup, drummer Shawn Drover and guitarist Chris Broderick left the band. It wasn't until April 2015 that Megadeth finally began recording in a Nashville studio with new guitarist Kiko Loureiro (Angra) and drummer Chris Adler (on loan from Lamb of God). Co-produced by Mustaine and Toby Wright and mixed by Josh Wilbur, it also contained orchestrations from celebrated Music City arranger Ronn Huff, father of producer Dann Huff. Mustaine leaked the art and track list for Dystopia in late July. In October, the pre-release single "Fatal Illusion" was issued, followed by the full-length in January of 2016. Dystopia would be the band's second highest-charting record, right behind Countdown to Extinction. The title track would also be awarded the 2017 Grammy for Best Metal Performance, making for Megadeth's first Grammy win after multiple fruitless nominations.

In 2018, the band unveiled a deluxe reissue of their debut, Killing Is My Business...And Business Is Good! The Final Kill. The set included a remastered edition of the original album; live cuts recorded in England, Germany, and the U.S. between 1986 and 1990; a three-track demo from 1984; and a rare cover, "These Boots." The next year Mustaine hand selected 35 tracks from the band's massive studio discography to be compiled into an anthology/greatest-hits collection entitled Warheads on Foreheads. The epic collection was released in March of 2019.

The band headed into the studio later that year to begin work on the follow-up to Dystopia but were met with an array of hardships. Mustaine was diagnosed with throat cancer, the Covid-19 pandemic cut short the group's 2020 tour, and longtime bassist Dave Ellefson was forced to leave the group in 2021 after sexually explicit videos of him and a young fan were posted online. Still, Mustaine vowed to keep the band afloat, and they worked on their 16th long-player, The Sick, The Dying... And the Dead!, from 2019 to 2022, when it was released. Ellefson's bass parts were removed from the album following his dismissal from the band, and new basslines were recorded by Testament's Steve Di Giorgio. In addition to being the first album to feature new drummer Dirk Verbeuren, The Sick, The Dying... And the Dead! included a cameo from Ice-T, and digital bonus tracks featured Sammy Hagar singing lead on a cover of his 1979 song "This Planet's on Fire (Burn in Hell)" as well as a rowdy rendition of the Dead Kennedys' "Police Truck." Six years passed between Dystopia and The Sick..., making it the longest stretch between studio album's in Megadeth's nearly 40-year history.