Trigun takes place in the distant future on a deserted planet. Vash the Stampede is a gunfighter with a legend so ruthless he has a $60,000,000,000 bounty on his head. Entire towns evacuate at the rumor of his arrival. But the real Vash the Stampede, the enigmatic and conflicted lead character in Trigun, is more heroic, even though he usually acts like a complete idiot.

I-Machines are the general term for robots that operate in extreme environments. While Alliance Academy student Maya Mikuri is in the middle of operating an I-Machine, she gets involved in an incident with pirates, and ends up serving as a crew member on an excavation company's spaceship.