Clinicians can choose among various second-generation antidepressants for treating depressive disorders, such as major depressive disorder, subsyndromal depression, or dysthymia. Systematic reviews indicate that available drugs differ in frequency of administration, costs, and the risks of some adverse events but have similar efficacy for treating major depressive disorder. Furthermore, evidence does not support the choice of one antidepressant over another based on accompanying symptoms, such anxiety, insomnia, or pain. Available studies provide little guidance for clinicians about the benefits of second-generation antidepressants for treating dysthymia and subsyndromal depression. Evidence is also unclear about the comparative risks of serious adverse events, such as suicidality, seizures, fractures, increased bleeding, or serotonin syndrome. This article summarizes the best available evidence regarding comparative benefits and harms of second-generation antidepressants for treating depressive disorders.