Major depressive disorder is a widespread, serious, chronic, and recurrent condition that imposes the burden of depressive symptoms and associated dysfunction and can ultimately lead to suicide. Psychopharmacological and specific psychotherapeutic interventions lessen the burden of depression, yet in modern clinical trials high placebo rates make efficacy difficult to prove. The mixed proof of efficacy has contributed to reassessments of the benefit-risk ratio of antidepressants and a reemergence of concerns that antidepressants can induce suicidality. In 2004, the Food and Drug Administration issued black box warnings on package inserts of antidepressants that, in some ways, state the obvious: patients with depression, especially children and adolescents, should be tracked carefully for exacerbations and suicidal ideation during treatment. In other words, physicians should take depression and its treatment seriously.