Conflict can profoundly affect individuals and their groups. Oftentimes, conflict involves a clash between one side seeking change and increased gains through victory and the other side defending the status quo and protecting against loss and defeat. However, theory and empirical research largely neglected these conflicts between attackers and defenders, and the strategic, social, and psychological consequences of attack and defense remain poorly understood. To fill this void, we model (1) the clashing of attack and defense as games of strategy and reveal that (2) attack benefits from mismatching its target's level of defense, whereas defense benefits from matching the attacker's competitiveness. This suggests that (3) attack recruits neuroendocrine pathways underlying behavioral activation and overconfidence, whereas defense invokes neural networks for behavioral inhibition, vigilant scanning, and hostile attributions; and that (4) people invest less in attack than defense, and attack often fails. Finally, we propose that (5) in intergroup conflict, out-group attack needs institutional arrangements that motivate and coordinate collective action, whereas in-group defense benefits from endogenously emerging in-group identification. We discuss how games of attack and defense may have shaped human capacities for prosociality and aggression, and how third parties can regulate such conflicts and reduce their waste.