Major depressive disorder ranks among the most significant causes of mortality and disability in the world. Recent data from the investigators and others highlight that impairments in reward and loss learning are central to depression, have distinct neural substrates, and improve with successful treatment. Together, these findings suggest an urgent need to delineate the relationships among neural and behavioral learning impairments and depression. Equally important, these insights suggest new targets for treatment such that manipulating the neural and behavioral substrates of learning may facilitate symptom change in depression.