Escaping prison and wanting revenge against Spider-Man, Doctor Octopus organized former wall-crawler foes Electro, Kraven the Hunter (Sergei Kravinoff), Mysterio (Quentin Beck), Sandman, and the Vulture into the Sinister Six. Though he promised a "foolproof plan", Octavius merely arranged the kidnapping of Betty Brant and, incidentally, May Parker, which enraged the wall-crawler into top fighting form. The contentious Six could only agree to attack Spider-Man individually, insuring their defeat.
Years later, Octopus reunited the group, coercing the reformed Sandman to join by threatening to kill the family with whom he boarded and replacing the deceased Kraven with Hobgoblin. His plan to steal a soon-to-be-launched satellite in order to spray poison into the atmosphere was actually a blind to spray a substance that caused convulsions in cocaine users. Octopus alone held the antidote, burundite, which he planned to sell to addicts, turning on his partners and keeping all proceeds for himself. The substance was successfully released but negated when Thor released the burundite in the upper atmosphere as well. The betrayed five teamed up to gain revenge on Ock but ended up joining him in a scheme to steal weapons and retrieve the immense Tsiln race's Gog from another dimension in order to take over Hydra's satellite setup. When Sandman rebelled, he was turned to glass and shattered by Ock; Gog took his place in the group. As Spider-Man, the Fantastic Four, Hulk (Bruce Banner), Sleepwalker, Nova (Richard Rider), Ghost Rider (Daniel Ketch), Deathlok (Michael Collins) and Solo (James Bourne) fought the others, a reconstituted Sandman attacked Octopus, nearly killing him.
Ock was later murdered by the Peter Parker clone Kaine, his tentacles and notes seized by the government. His cousin Elias Hargrove, an unwitting dupe of Mysterio who manipulated the others for his own ends, reunited the surviving members, minus Sandman, to retrieve these possessions, but Spider-Man, the Scarlet Spider (Ben Reilly) and Kaine ruined the scheme. Frightened by Kaine's murders of other Spider-Man foes, Electro, Hobgoblin, Mysterio and Vulture joined with Beetle, Shocker and Scorpia to form the Sinister Seven. They hoped to stop Kaine by attacking him first but were nearly killed in the encounter. The Six, including a resurrected Dr. Octopus, were later regathered for an elaborate, yet ultimately futile, plot to destroy Spider-Man and gain immeasurable wealth by destroying the world's monetary system.
Still angered over his treatment by Dr. Octopus, the Sandman, reverted to evil by the Wizard's id machine, reorganized the group, with Daniel Berkhart replacing the deceased Quentin Beck as Mysterio, Alyosha Kravinoff appearing as the new Kraven, and Venom (Edward Brock) horning in as the sixth member. They attacked Ock and Senator Stewart Ward, only to be repelled by Ward's alien-implanted powers.