There is a mystery surrounding the disappearance of short-finned pilot whales (Globicephala macrorhynchus) from southern California. This species was very common in these waters through the early 1980s, with an apparently seasonally-resident population centered around Santa Catalina Island in the Southern California Bight. From 1980-1985, pilot whale numbers off Catalina Island declined dramatically, and they eventually disappeared. One theory has been proposed for this phenomenon, suggesting that a strong El Niño event in 1982/83 resulted in a failure of their main prey, market squid (Doryteuthis opalescens), which lead to their departure. However, we argue that previously underestimated impacts from fishery by-catch and other anthropogenic effects may have actually been the primary driver. Information from diverse sources show that from the 1950s to 1980s, pilot whales were subject to extensive by-catches in purse-seine nets, lampara nets, and oceanic driftnets, as well as intentional shooting by fishermen, and live-captures for the aquarium industry. As a result, dozens of animals may have been removed in some years. From 1952 to 2014, we have documented no less than 232 individuals removed from southern California, with >52% through known anthropogenic factors. If these removals primarily affected the Catalina Island ‘residents’, they would have had a severe impact on that population. We conclude that human interactions of various types almost certainly played an important, and previously unrecognized, role in the disappearance of short-finned pilot whales from southern California waters.