A wide variety of antidepressants are available today for treating major depressive disorder. However, like all medical therapies, antidepressants have several limitations that clinicians should consider when choosing treatments for their patients. This article reviews the efficacy, tolerability, and safety of the newer (ie, posttricyclic era) antidepressants. Specifically, overall efficacy and efficacy in relation to specific depressive symptoms and patient subpopulations, as well as in relation to various psychiatric and medical comorbidities, are addressed, along with tolerability profiles with respect to common side effects, including nausea, fatigue, insomnia, somnolence, sexual dysfunction, and weight gain. Finally, the safety profile of these agents is summarized.