The tour began in the fall of 1990 with a three-week European leg featuring Megadeth, Slayer, Testament and Suicidal Tendencies, promoting their then-current albums Rust in Peace, Seasons in the Abyss, Souls of Black and Lights...Camera...Revolution! respectively.
A second leg in 1991 in the United States and Canada had a slightly different lineup: Megadeth, Slayer and Anthrax headlined, and Alice in Chains supported; while Megadeth and Slayer were still promoting their respective albums Rust in Peace and Seasons in the Abyss, Anthrax was supporting their fifth studio album Persistence of Time and Alice in Chains was touring behind their debut album Facelift. Testament was the opening act for the May 26, 1991 show at the Cow Palace in Daly City, effectively reuniting three-fourths of the European lineup.
Alice in Chains was not originally on the bill for the U.S. tour. According to the documentary Get Thrashed, Death Angel was to be the supporting act – however, after a near-fatal tour bus crash, they were forced to bow out. Sepultura was also mooted for the tour, but, according to then-frontman Max Cavalera, "got kicked out", and instead embarked on the New Titans on the Block tour with Sacred Reich, Napalm Death and Sick of It All. Anthrax guitarist Scott Ian stated in an interview with Guitar World that they wanted Pantera as the opening act of the Clash of the Titans tour. Other bands, such as Exodus, Vio-lence, Kreator and Obituary, also reportedly declined to take part in the tour as the opening act.
"We didn't start making any money until 1991, on the Clash of the Titans tour in the States – not even a dime," recalled Ian. "I got home from that tour to receive a cheque for a sizeable amount and called my accountant, saying, 'There must be a mistake.' We were of Iron Maiden's style of mindset, where we had to have these huge stage sets, and everything went straight back into the band."
Interesting to note is that Metallica was the only "big four" of thrash metal act that did not take part in the Clash of the Titans tour. Slayer guitarist Kerry King told Guitar World that, "There might have even been talk of a 'Big Four' tour back then, but we probably couldn't get Metallica onboard. But we had three pieces of it, and that was all the management and promoters needed." Anthrax drummer Charlie Benante and Megadeth bassist David Ellefson have indicated that one of the reasons Metallica was not part of the Clash of the Titans tour was due to their ascension to popularity, specifically with their self-titled "black album", which was not released until five weeks after the tour's conclusion. King added, "I knew Metallica wouldn't be a part of it 'cause they didn't need us."
On November 16, 2009, it was announced that the European Clash of the Titans lineup would be reunited after nineteen years on the American Carnage Tour, featuring Megadeth, Slayer and Testament. On July 13, 2010, a second leg of the American Carnage Tour was announced that would feature the American Clash of the Titans lineup: Megadeth, Slayer and Anthrax. Neither Suicidal Tendencies nor Alice in Chains featured in either lineup.
On December 9, 2017, Ultimate-Guitar.com reported that a rebooted Clash of the Titans tour featuring Megadeth, Slayer, Testament and Sepultura was in the works, and scheduled to take place in 2018 or 2019 in support of new albums from these four bands. More speculation about a tour similar to Clash of the Titans was renewed in January 2018, when Megadeth frontman Dave Mustaine mentioned a potential tour featuring Exodus and three of the "big four" (Megadeth, Slayer and Anthrax); a month later, Mustaine another potential tour similar to Clash of the Titans, titled "The New Big 4", featuring Megadeth, Anthrax, Exodus and Testament.
When Slayer announced their farewell tour in January 2018, it was suggested that the recently-rumored Clash of the Titans tour (also featuring Megadeth, Sepultura and Testament) would take place as part of the aforementioned tour. Although Mustaine cryptically denied that this tour was in the works, he stated in a June 2018 interview with Rock Talk With Mitch Lafon that, "I hope that Megadeth and Slayer get to go one more round somewhere. I think it would be great, especially if it was a 'Big Four' show, but that's entirely up to them. And if it doesn't happen, we've had our share of Slayer and Megadeth shows, and I'll always appreciate those times together." Testament frontman Chuck Billy also commented on the tour rumors, referring to Slayer's farewell tour, "I doubt it, this is Slayer's last tour so this is it. There will be no more Slayer tours, ha ha."
When asked in August 2018 by CBS San Francisco about the possibility of a new Clash of the Titans tour with Slayer and Megadeth, Anthrax bassist Frank Bello stated, "I wouldn't say it's under wraps because I don't know about it. But I would absolutely love for the Big 4 thing to happen again. That would be the right thing to do for everybody. I would love that. I mean, as far as Slayer goes, I'm sure they're going to do more shows next year, but I don't know if we'll be on them, because we do have our album to write. It's all about scheduling and agents and all that. But we'd be open to any of that, specifically the Big 4. I think all four bands that were involved with the Big 4 would love to do it again. But that's totally up to Metallica."