Theoretical models based on primate evidence suggest that social structure determines the costs and benefits of particular aggressive strategies. In humans, males more than females interact in groups of unrelated same-sex peers, and larger group size predicts success in inter-group contests. In marked contrast, human females form isolated one-on-one relationships with fewer instrumental benefits, so social exclusion constitutes a more useful strategy. If this model is accurate, then human social exclusion should be utilized by females more than males and females should be more sensitive to its occurrence. Here we present four studies supporting this model. In Study 1, using a computerized game with fictitious opponents, we demonstrate that females are more willing than males to socially exclude a temporary ally. In Study 2, females report more actual incidents of social exclusion than males do. In Study 3, females perceive cues revealing social exclusion more rapidly than males do. Finally, in Study 4, females' heart rate increases more than males' in response to social exclusion. Together, results indicate that social exclusion is a strategy well-tailored to human females' social structure.