Hank and Dean Venture, with their father Doctor Venture and faithful bodyguard Brock Samson, go on wild adventures facing megalomaniacs, zombies, and suspicious ninjas, all for the glory of adventure. Hank and Dean Venture are relatively identical twins, only born six minutes apart, who live for the thrill of adventure. Their dated vocabulary and high-pitched voices are intentionally annoying, especially to their father, Doctor Venture, a boy genius turned mediocre scientist who hates everything about his life. In the midst of this conflict is Brock Samson, a man of swift neck-breaking action. Preferring to resort to his brawn instead of his brain, Brock is simple but effective, and does a better job at taking care of the kids than Doctor Venture.
Brock Samson leaves to try and get revenge on Col. Gathers while Nazis want Dr. Venture to clone Hitler from the blood of a dog. Twenty-one deals with the death of Twenty-four and Sgt. Hatred becomes the new Venture bodyguard. Hank and Dean deal with Brock leaving.
The Monarch and Sgt. Hatred close in on the Venture Family, who are forced to flee after the hotel battle with Le Tueur. Meanwhile, the OSI still want Brock dead and will go to any lengths to accomplish it.
The OSI has put a termination contract on Brock's head, and three top assassins plan to collect. Meanwhile, the Monarch and Sgt. Hatred battle to see who will be Dr. Venture's arch.
Billy Quizboy has spent thirty years trying to decipher a series of cryptic clues hidden in Rusty Venture Cartoon Show episodes. Finally the solution to the mystery is at hand, but the answer forces Brock to discover what his true orders are.
The Monarch launches his first attack on his new arch nemesis, the other Dr. Venture. But Jonas has the formidable defenses of Spider-Skull Island on his side, as well as his own Team Venture, and the expert advice of a trio of O.S.I. butterfly specialists.