Toonami was slowly growing into a popular block, but it needed that extra kick to the lineup. In the spring of 1998, Toonami aired the popular computer-animated series Transformers: Beast Wars for a trial one-week period. The ratings were phenominal for the block and convinced Cartoon Network to form a corporate friendship with Hasbro (Beast Wars' owners) and Mainframe (the show's producers). By the summer of 1998, Toonami became the exclusive home to Beast Wars, and aired the final season during the fall of that year as a Friday exclusive. In August 1998, Cartoon Network acquired the broadcast rights to a pair of Mainframe titles, the new sci-fi drama series War Planets and the action-comedy series ReBoot. War Planets began in the winter of 1998 while ReBoot made its Toonami debut in March 1999.

Toonami also became the exclusive home of Batman: The Animated Series and Super Friends in the fall of 1998. The shows brought the DC Animated Universe to the block for the first time ever. A year later, Superman joined the Toonami block. 1999 also brought a revamped version of Beast Wars, known as Beast Machines, which stayed on the Toonami block until 2001 when Hasbro, under Cartoon Network's direction, returned the Transformers franchise to the classic Autobots versus Decepticons rivalry.

Toonami co-produced the dubbed version of Transformers: Robots in Disguise and premiered it in the fall of 2001. 2001 proved to be one of the biggest years in the history of Toonami. Batman Beyond and The Powerpuff Girls also migrated to Toonami in the fall, and the year also brought a pair of new original series to the Toonami block. Samurai Jack, a highly-stylized action series from Genndy Tartakovsky, creator of Dexter's Laboratory, and Justice League, the first team series from the creators of Batman: The Animated Series, both premiered on Toonami in 2001.

For the next several years, ratings only began to grow on the Toonami block. The success of Transformers on Toonami convinced Mattel to revamp their own classic action franchise Masters of the Universe in 2002. That year, Toonami picked up and co-produced a new version of He-Man and the Masters of the Universe. The block also began looking at other titles from all over the world, including taking a second look at Japan. In 2003, Cartoon Network acquired a trio of shows from Sunrise Animation, a pair of space-themed action series (Outlaw Star and Cowboy Bebop, which both became part of the Toonami Midnight Run block in a fairly uncut form) and The Big O, which was paired off with classic episodes of Batman: The Animated Series in the 5:30 PM slot on the block.

This broadcasting partnership allowed Toonami to have a exclusive first-look window of the entire Sunrise library of shows via Sunrise's American distributor, Bandai Entertainment. The title they picked up in 2003 was the one the studio was currently working on at the time: Gundam SEED, which became a major part of the Toonami extension to Saturday nights a year later. Gundam Wing became a mainstay on the weekday lineup beginning in the fall of 2003 while the classic Mobile Suit Gundam formed the final half hour of the now two-hour Toonami Midnight Run.

Toonami also became the exclusive home of Totally Spies, Code Lyoko, Class of the Titans, and a pair of new Cartoon Network originals, Teen Titans and Megas XLR. 2004 brought Star Wars to Toonami in the form of the Clone Wars, Toonami's first microseries event. The block also optioned the rights to broadcast the new Star Wars animated series in 2008.

Cartoon Network licensed their popular Powerpuff Girls to Toei Animation in 2005. In exchange, Toei gave Cartoon Network exclusive international rights (except for Japan) to a trio of their biggest properties, two of which licenses had just expired in the US: their current hit One Piece, Sailor Moon, and Dragon Ball Z.

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