Veteran reporter Roberto and rookie Meryl find themselves helping Vash the Stampede, an infamous thief with a bounty of six million double-dollars on his head.

Vash is in danger again now that ordinary townsfolk who have heard about the bounty are after him. As Vash tries to leave town, he runs into a family of heinous criminals who have broken out of prison and are now in a race to claim the bounty on his head.

Vash meets Nicholas, a suspicious undertaker who carries a huge cross. Before they could get to know each other, though, they are attacked by a huge worm, swallowing them and the building they were in.

Vash is drawn towards a seemingly abandoned village with a giant windmill, for reasons that only he knows. There, the group is attacked by a tremendous gale of gunfire.

Vash and Wolfwood board the massive Sandsteamer vessel to travel to their final destination, JuLai. Yet again, they are ambushed by a hail of gunfire, but this time, it's someone Wolfwood knows.

Vash and Wolfwood work together to stop Livio, an assassin who has lost his sense of self. The chaos is further accelerated by an attack by the Bad Lads Gang. While this is happening, someone sabotages the Sandsteamer, sending it on a crash course with Hopeland, Wolfwood's home town.

Many years in the past, a colony ship traveling through space to find a new home for humanity suddenly experienced an emergency. Young Vash and Knives were saved by Rem and crash-landed on the planet No Man's Land on an escape pod.

After surviving the crash, Vash started a life with Luida and Brad, while Knives formed an alliance with Conrad, the leader of the research group called the Sinners. The twins finally meet again in front of an array of plants that have turned red from overwork.

Meryl and Roberto are taken to JuLai, the Third City, by Zazie. There, they learn why and how the human race ended up on this planet, No Man's Land. They also see Conrad, the former leader of the Sinners research group, who explains his goals. Meanwhile, Vash and Wolfwood reach the top floor of the JuLai Tower, where Knives awaits.

Caught in Knives' trap, Vash is dropped into a giant pool. There, Knives attacks the precious memories that helped Vash maintain his love towards humanity. While Vash and Knives clash in this metaphysical realm, Meryl witnesses the astonishing physical manifestations.