The payload of antibody–drug conjugates (ADCs) is the warhead of ADCs that kills the tumor cells. Five classes of cytotoxins including maytansinoids, auristatins, calicheamicins, pyrrolobenzodiazepine dimers, and camptothecins are employed as the payloads in a total of 12 ADCs currently approved by the FDA. The structures, mechanisms of action, and pharmacology of these small-molecule cytotoxins are reviewed and discussed. The payloads along with the approved ADCs and their therapeutic areas are summarized.