NPY antagonizes behavioral consequences of stress through actions within the brain. Behavioral anti-stress actions of NPY are noteworthy in that (1) their magnitude surpasses that of other endogenous compounds; (2) they are produced across a wide range of animal models, normally thought to reflect different aspects of emotionality. This suggests that NPY acts with a high potency on a common core mechanism of emotionality and behavioral stress responses. Behavioral studies in genetically modified animals support this hypothesis. Increased emotionality is seen upon inactivation of NPY transmission, while the opposite is found when NPY signalling is made overactive. Several brain structures are involved in mediating anti-stress actions of NPY, with the most extensive evidence available for amygdala and hippocampus, and some evidence for regions within the septum, and locus coeruleus. Antistress actions of NPY are mimicked by Y1-receptor agonists, and blocked by Y1 antagonists, although Y5 receptors may substitute for Y1 actions in some cases. Blockade of Y2 receptors produces anti-stress effects indistinguishable from those produced by Y1 agonism, presumably through potentiation of presynaptic release of endogenous NPY. Together, available data point to the potential of the NPY system as a target for novel pharmacological treatments of stress-related disorders, including anxiety and depression. Development of Y2 antagonists presently appears to offer the most promising strategy for developing these clinical treatments.