Some of Sin City's most hard-boiled citizens cross paths with a few of its more reviled inhabitants.

Gregorio and Ingrid Cortez are rival spies who fall in love. They retire and have two children, 12-year-old Carmen and 9-year-old Juni. They work for the Organization of Super Spies (OSS) doing desk work. The children have no idea of their parents' previous career. Gregorio and Ingrid are called back into the field when agents go missing. The children are left in the care of their uncle Felix. Gregorio suspects that children's television host Fegan Floop has kidnapped the agents and mutated them into his "Fooglies," creatures on his show.

Machete and Sartana Rivera attempt to capture weapon dealers who have been supplying the Drug cartel. The military men are then all killed by the gangsters, who in turn are wiped out by another intervening party. Its leader murders Sartana while Machete is arrested by corrupt Sheriff Doakes and Deputy Clebourne. Doakes unsuccessfully tries to hang Machete but the President of the United States, Rathcock, intervenes. Machete is brought to the White House, where the president offers him US citizenship if he eliminates Marcos Mendez, a psychopath who is threatening to fire a nuclear missile at Washington, D.C. if the American government does not intervene to stop the rampant drug cartels in Mexico and the corruption of its government.