Zs'Skayr made his debut after Ghostfreak escaped from the Omnitrix. Zs'Skayr attempts to possess John right away, but is sealed in a time prison, allowing John the time to escape, but didn't hold Zs'Skayr indefinitely.
Zs'Skayr returns as a member of the Separatists, having turned the citizens of Revonnah into Ectonurites like himself. John leads an army of clones to fight, and engages in single combat with him. After rescanning him, John defeats Zs'Skayr with a powerful burst of light, destroying him.
When Ghostfreak was re-unlocked, Zs'Skayr was trapped in the Omnitrix again. When Azmuth removed the safeguards in an attempt to unlock the ultimate forms, Zs'Skayr tried to take control of John and get free. The Omnitrix then locked John in Ultimate John, Zs'Skayr still trying to get free.
John learns this as he attempts to use Ultimate John again, where Zs'Skayr attempts to take control. He's repelled, but he had already taken over the mind of Rogue, a member of the X-Men who had absorbed John's powers, and in doing so, Zs'Skayr's consciousness. Zs'Skayr uses her absorption powers to drain the Omnitrix, and Rogue mutates similar to how Kevin does. John is able to reverse the effects, and force Zs'Skayr out. He's then destroyed by sunlight.
Zs'Skayr, his consciousness becoming dormant in Kevin after he absorbed John's energy, is released by Phantom and joins the New Chess Pieces, becoming a Knight. He is John's final opponent in the War Games, where he's once again defeated and destroyed.
Much later, Zs'Skayr is revived after Intellectuary taps into a Puppet John, allowing Zs'Skayr to break free and take control of this body. By Intellectuary's request, he works with Lord Transyl to release a corrodium wave throughout the shattered dimensions, corrupting everyone to serve them and by extension Intellectuary. John, Kai and Yenal battle the two, as John destroys Zs'Skayr again.
Zs'Skayr, as Ghostfreak, located Dr. Viktor at Area 51, and gave him a plan to initiate. After everything was in place, Ghostfreak escapes the Omnitrix, becoming Zs'Skayr. He takes over the SACT base in an attempt to use the satellite to launch nuclear missiles to wipe out humanity. Ryder and Lt. Steel manage to stop him long enough for the sun to destroy him.
After Viktor escapes from the Null Void, he initiates a plan and successfully revives Zs'Skayr. Zs'Skayr then continues his plan to take over the Earth, with Ryder getting caught up in it. He plans on corrupting the Earth with Corrodium, which is stopped.
Zs'Skayr returns later, having used hedorium to form a portal home, summoning an army of Ectonurites. Ryder sends the invasion force back and banishes Zs'Skayr to Ledgerdomain. Years later, as Ryder enters the magic realm again, Zs'Skayr escapes with the Alpha Rune and returns home, reviving Lord Transyl with the rune. Ryder appears to take the rune back and destroys Zs'Skayr again.
