Major depressive disorder (MDD) is commonly encountered in clinical practice but is often underdiagnosed and undertreated, in part because many patients present only with vague somatic complaints instead of typical depressed symptomatology. Once diagnosed, patients with MDD can be treated with pharmacologic and/or nonpharmacologic therapies, but it is difficult to predict how or whether an individual will respond. Studies have shown that the majority of depressed patients fail to remit with initial therapy and, even if remission is achieved, many patients will relapse. While the management of patients with MDD presents challenges, data indicate that the achievement and maintenance of remission can be improved by frequent follow-ups with a clinician who can provide individualized education/support and appropriate referral to other healthcare specialists. Novel pharmacotherapies that are formulated for oncedaily dosing with improved safety profiles can improve adherence to treatment and reduce the morbidity and mortality associated with MDD.