Depression and bipolar disorder are the most common mood disorders. Recognizing how the mood system works more broadly is foundational for understanding these disorders. While emotions tend to be short-lived, somewhat automatic reactions to specific external stimuli, moods last longer, are caused by several factors, and tend to have more all-encompassing effects on motivation and behavior. An evolutionary behavioral perspective on the mood system views mood as a dynamic psychobehavioral regulatory mechanism, calibrated according to the inputs it receives from the environment in order to produce behavioral outputs that more adaptively fit the perceived balance between rewards and punishments in one’s environment. In depression, mood becomes unnaturally low, leading to a distorted perception of fewer rewards and more frequent punishments in the environment. The psychophysiological stress system, including the hypothalamic–pituitary–adrenal (HPA) axis, is one proximate mechanism that mediates the relationship between environmental inputs (e.g., those that cause stress) and changes in mood. This system might be overactive in people living in contemporary environments that have many evolutionarily novel stressors. This creates the physiological basis for the way in which major individual stressors as well as chronic stress are implicated in the pathophysiology of depression in contemporary Homo sapiens.