While enormous progress has been made in unraveling the proximate physiological mechanisms that account for anxiety, stress, and low mood, these states continue to give rise to considerable conceptual confusion. This is, in part, because proximate studies have neither been adequately distinguished from, nor integrated with, evolutionary explanations for the adaptive functions of anxiety, stress, and mood. A complete biological explanation that incorporates both proximate and evolutionary explanations will be of great value to better define the border between normal and pathological, to help to explain why pathological anxiety and depression are so common, and to provide a much-needed basis for sensible decisions about when different pharmacological manipulations are likely to be helpful or harmful. Ideally, evolutionary considerations should provide a conceptual framework within which the biological significance of the proximate mechanisms can be better understood, and the proximate findings should provide tests of evolutionary hypotheses. Studies at the interface between evolutionary and proximate explanations will be difficult, but important to better understand individual differences in vulnerability and the etiology of diseases that result from dysregulation of anxiety and mood.