Mood disorders, particularly major depression, are the most frequent complication of traumatic brain injury. Major depression is present in about 40% of patients hospitalization for a traumatic brain injury. Anxiety disorders, substance abuse, dysregulation of emotional expression, and aggressive outbursts are frequently associated with major depression, and their coexistence constitutes a marker of a more disabling clinical course. The complex interactions of genetic, developmental, and psychosocial factors determine patients' vulnerability to developing affective disturbances following a traumatic brain injury. Symptoms of depression cluster into the domains of low mood and distorted self-attitude, lack of motivation and anhedonia, subjective cognitive complaints, and hyperactive and disinhibited behavior. It is reasonable to assume that these symptomatic clusters have specific underlying mechanisms that need to be integrated in a comprehensive pathophysiologic model.