Sertraline is a highly specific, potent inhibitor of serotonin reuptake. It exerts no clinically significant effects on norepinephrine and dopamine uptake and possesses negligible binding affinity for histaminergic, muscarinic, dopaminergic, and adrenergic receptors. Its pharmacologic profile permits once-daily dosing while allowing plasma drug levels to equilibrate within 1 week. In multicenter, double-blind trials, sertraline proved superior to placebo and comparable to amitriptyline in ameliorating acute depression. Moreover, the drug has been shown to be effective in preventing relapses of the index episode and recurrence of further episodes over the long term. Sertraline has not been associated with sedating or anticholinergic effects, psychomotor impairment, or cardiovascular toxicity. Its principal side effects are generally transient and include mild-to-moderate nausea or diarrhea and sexual dysfunction (ejaculatory delay) in males. The safety margin of sertraline is wider than that of the tricyclic antidepressants. This serotonin reuptake inhibitor shows promise as an important therapeutic and prophylactic alternative in the pharmacologic management of depression.