Over the past few decades, there has been increasing recognition of the problem of persistent, or chronic, depression. Chronic depressions account for up to a third of the cases of depression in the community and half the cases in clinical practice. Moreover, as reflected in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), persistent depressive disorder differs in many significant respects from nonpersistent depression. This chapter provides an overview of the current literature on persistent depression, starting with classification, epidemiology, and course. Psychosocial and neurobiological risk factors, including early adversity, genetics, personality/temperament, cognitive style, interpersonal difficulties, neural abnormalities, and chronic stress, are then reviewed. Next, we discuss psychopharmacological and psychotherapeutic interventions for acute and continuation/maintenance treatment of persistent depression. We conclude with suggestions for future research.