The game opens with Ratchet and Clank finding a news report about Ratchet’s home planet, Veldin, which is under attack by an army of aliens named Tyhrranoids.[15] The lead suspect is a mysterious villain by the name of Dr. Nefarious. After they help to defeat the Tyhrranoids on Veldin, the Galactic President tells Ratchet that Captain Qwark, an enemy from the first two games in the series, is the only person to ever have defeated Dr. Nefarious and that Qwark’s help is needed to defeat him again. Ratchet finds a now-feral Qwark living in the jungle, and takes him to the Starship Phoenix, whose commander has been ordered to help Ratchet and Qwark defeat Dr. Nefarious.[16] Upon having his memories restored, Qwark creates the “Q-Force”, a team of “elite” soldiers working against Dr. Nefarious, and assigns Ratchet a new mission to infiltrate Nefarious’ base[17] and acquire as much information on Nefarious’ plans as possible. They find out that Dr. Nefarious is a fan of ‘Secret Agent Clank’, Clank’s TV show, along with an encrypted star map to the Tyhrranoids’ home planet.[18] After the Q-Force destroys a Tyhrranoid hive on their home planet, Dr. Nefarious sends the Q-Force a transmission[19] mocking them and telling them that they won’t be able to defeat him; Al traces the transmission to planet Daxx.
Ratchet and Clank arrive at Daxx and learn about something called a Biobliterator, but not what it does.[20] They also find a music video by Courtney Gears (a parody of Britney Spears), which tells robots to destroy organic lifeforms. Ratchet and Clank investigate Courtney Gears’ activities, but she manages to charm and eventually kidnap Clank. Unbeknownst to Ratchet, she hands Clank over to Dr. Nefarious. Nefarious gives Clank the choice to either rule the Universe with him or to be a disgrace to all robots by pairing with the organic life forms;[21] Clank refuses Nefarious’ offer. Unknown to both Ratchet and the game’s player, Dr. Nefarious replaces Clank with an evil twin named Klunk, while holding Clank prisoner. Ratchet, with Klunk, then follows up on the Bioblierator on the Obani Moons. While helping them access the third of the moons, Skidd, another member of the Q-Force, is kidnapped by Courtney Gears. Ratchet enters the third moon to save him, but is too late as Skidd gets transformed into a robot.[22] Courtney Gears attempts to do the same to Ratchet, but Ratchet fights and defeats her before she gets the chance. Meanwhile, Sasha tracks down Dr. Nefarious on a Star Cruiser called The Leviathan and upon Ratchet’s return she sends him and Qwark to infiltrate the ship.[23] When Ratchet arrives, however, he discovers that Dr. Nefarous lured them to the ship as a trap, and he activates the self-destruct system before teleporting out.[24] Qwark says he may have found intel and, much to Ratchet’s dismay, Klunk asserts that they must leave him behind. The duo escape just as the Leviathan explodes.[25]
While Ratchet is fighting off yet another Tyhrranoid invasion in the city of Metropolis, Nefarious uses the Biobliterator to turn the helpless citizens and Tyhrranoid invaders alike into robots. Before Ratchet can attack him, Dr. Nefarious escapes the city and Klunk attacks Ratchet. After defeating Klunk, Ratchet and Clank are reunited, and discover that Captain Qwark is still alive and is hiding at his secret hideout,[26] but they cannot convince him to rejoin the fight against Dr. Nefarious. Ratchet and Clank reach another one of Nefarious’s hideouts and Clank destroys the Biobliterator. However, Sasha soon reports that a second Biobliterator is housed at Nefarious’s main command center on planet Mylon,[27] Ratchet and Clank arrive at the command center and confront Nefarious, but before they can defeat him he teleports inside the Biobliterator, which transforms into a giant, heavily armed robot. Having regained his bravery, Captain Qwark flies in to fight alongside them and they engage in aerial combat against Nefarious and the Biobliterator and defeat it. The Biobliterator self-destructs, and Nefarious and Lawrence (his butler) are left stranded on an asteroid after attempting to teleport away from the explosion.[28] The ending fades to the Q-Force and their allies watching the premiere of the latest Secret Agent Clank holofilm.