Major depressive disorder is present in 15%-20% of patients with diabetes and impairs functioning and quality of life. It has unique importance in diabetes because of its association with poor compliance with diabetes treatment, poor glycemic control, and an increased risk for micro- and macrovascular disease complications. These observations have inspired several recent clinical trials to determine whether these associations may be favorably influenced by depression treatment. The outcome data are scant but promising and suggest that psychotherapy and pharmacotherapy can have important positive effects on both mood and glycemic control. Unfortunately, even after successful treatment, recurrence of depression is the norm. Afflicted subjects are seldom asymptomatic for an entire year at a time. Factors related to the medical illness (eg, presence of diabetes complications, hyperglycemia) are associated with a poorer prognosis for recovery from depression, a finding that suggests that optimal relief of depression in diabetes may require vigorous, simultaneous management of the medical and psychiatric conditions. Whether maintenance antidepressant treatment is useful in preventing depression recurrence and promoting better glycemic control in diabetes is unknown, but this question is the focus of an ongoing clinical trial.