In summary, MDD is a highly prevalent major medical whose pathophysiology is still poorly understood. MDD is often recurrent or chronic, and evidence suggests that genetic factors partially influence overall risk of illness but also influence the sensitivity of individuals to the depressogenic effects of environmental adversity. Treatment with antidepressants, ECT, or certain forms of psychotherapy is fairly effective, but a substantial proportion of patients do not respond adequately, thereby requiring subsequent interventions. There are still many unanswered questions about MDD: (1) What are the susceptibility genes and their environmental modifiers? (2) What are the pathophysiologies of the neural systems underlying this complex disorder? (3) How do we understand the therapeutic mechanisms underlying the currently available pharmacological and ECT approaches? And (4) how do we improve our success rate in treating this highly disabling medical condition and how can we develop more rational algorithms for those who do not respond to standard treatments? Future investigations need to keep these issues in mind.‡To whom correspondence should be addressed (e-mail: mfava@partners.org [M. F.], kendler@hsc.vcu.edu [K. S. K.]).