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This article contains plot details.
The story begins with Ratchet and Clank playing a game in Clank's apartment in the Bogon galaxy. An episode of Clank's show, Secret Agent Clank, comes on and Ratchet is less than pleased. However, the show is interrupted by a news report. Ratchet's home planet, Veldin, is under attack by an army of Tyhrranoids. Dr. Nefarious is believed to be behind the attack. Ratchet and Clank then hurry back to the Solanna galaxy.
After helping the Galactic Rangers defeat the Tyhrranoids on Veldin, the Galactic President tells Ratchet that Captain Qwark is the only one who ever stopped Dr. Nefarious. As such, his help is needed to defeat him again. Ratchet finds Qwark on a jungle planet, and due to a MegaCorp experiment, he has lost his mind, thinking he is a giant ape.
Ratchet and Clank take Qwark to the Starship Phoenix, whose commander, Captain Sasha, has orders to help the duo and Qwark defeat Dr. Nefarious. After regaining his memories and his sanity, Qwark creates a team called the "Q-Force". Ratchet is assigned to infiltrate Dr. Nefarious' base on Aquatos and find out as much information as possible. While there, Ratchet and Clank find out that Nefarious is a fan of the Secret Agent Clank show and find a map to the Tyhrranoids' home planet. The duo destroy a base on the planet and a transmission from Nefarious is sent to the Q-Force. The doctor says that they can't defeat him and the transmission is traced to Planet Daxx.
On the planet, Ratchet and Clank learn about a machine called the Biobliterator, but they don't find out what it does. They also come across a music video by a galactic celebrity, Courtney Gears. The music video tells robots to kill all organic life in the galaxy. The duo investigate what Courtney Gears is up to but Clank gets kidnapped by her and taken to Nefarious.
Nefarious tells Clank that he can either rule the universe with him or be a disgrace to all robots by side with the organics. Clank refuses and Nefarious replaces Clank with an evil doppelganger called Klunk. Ratchet, unaware of what happened, takes Klunk with him and they follow up on the Biobliterator. This takes them to the Obani Moons. They meet up with Skidd, who is later kidnapped by Courtney Gears.
After getting access to the third moon, Ratchet comes across a screen where a video of Skidd being turned into a robot is played. Courtney attempts to turn Ratchet into a robot as well but she is defeated. During this, Sasha has tracked down Nefarious on a Star Cruiser called The Leviathan. She sends him and Qwark out to infiltrate the ship.
It turns out that Nefarious has lured them into a trap. He activates a self-destruct sequence before teleporting out. Qwark stays on the ship, having seen something and Ratchet and Klunk fly off as the ship explodes with Qwark on it. A funeral is held for Qwark aboard the Phoenix.
The Tyhrranoids soon invade Metropolis and Ratchet goes to fight them. Nefarious then uses the Biobliterator to turn the whole planet, except for Ratchet, into robots. Dr. Nefarious escapes the city and tells Klunk to defeat Ratchet. Once Klunk is defeated, Ratchet is reunited with Clank and they discover that Qwark is still alive but wants everyone to think he's dead.
Ratchet keeps that fact a secret, not wanting the others to lose hope. Clank reluctantly agrees and they manage to track Qwark down tat his secret hideout. Qwark refuses to rejoin the fight and Ratchet leaves, disgusted that he ever looked up to Qwark. Clank tells Qwark that he can still redeem himself and leaves.
The duo reach another base belong to Nefarious. Making it through the place, Clank destroys the Biobliterator. However, Sasha report that there is a second Biobliterator at Nefarious' command center on Planet Mylon. Fighting their way through the command center, they confront Nefarious. However, before he is defeated, he teleports into the Biobliterator, which turns into a giant robot. Qwark flies into battle with them and they defeat the second Biobliterator. It then self-destructs and Nefarious is stuck on an asteroid with his robot butler, Lawrence. At the end of the game, the cast attend a screening of the newest Secret Agent Clank film.
The game received critical acclaim at its release.
- The small idea for the show Secret Agent Clank actually turned out to be the new idea for the game.
- The cover art for the North American version of the game was reused for a spin-off game in the series.
- One of the returning weapons from Ratchet & Clank: Going Commando, the Lava Gun, has a new final upgrade. Instead of upgrading into the previous game's Meteor Gun, it now upgrades into the Liquid Nitrogen Gun.
- Data from the previous games can be accessed to give players perks.
- Data from the first game will unlock the "Old School Ratchet" skin and, if Kalebo III has been cleared, give out discounts for Gadgetron weapons.
- Data from the second game will cause the returning Megacorp weapons to be free as long as players have already acquired them.