Major depressive disorder is a significant public health problem and the leading cause of suicide worldwide. Since the discovery of the first effective medications for depression in the late 1950s, a variety of pharmacotherapies have been developed that are useful for treating the full range of depressive disorders. The availability of safer classes of antidepressants, as well as other factors, has resulted in a large increase in the number of depressed individuals who are treated for depression by their primary care providers. This review examines the antidepressants that are currently used as the initial or "first-line" therapies for major depressive disorder (MDD). These newer medications may be grouped into three classes: the selective serotonin reuptake inhibitors, the serotonin and norepinephrine reuptake inhibitors, and the norepinephrine-dopamine reuptake inhibitor. While the modern classes of antidepressants offer superior tolerability and safety over older medications such as the tricyclic antidepressants, there remains no universally effective pharmacologic treatment for MDD, and effective disease management requires careful attention to ongoing assessment of medication response and management of side effects.