From 2 to 10 percent of women of reproductive age have severe distress and dysfunction caused by premenstrual dysphoric disorder, a severe form of premenstrual syndrome. Current research implicates mechanisms of serotonin as relevant to etiology and treatment. Patients with mild to moderate symptoms of premenstrual syndrome may benefit from nonpharmacologic interventions such as education about the disorder, lifestyle changes, and nutritional adjustments. However, patients with premenstrual dysphoric disorder and those who fail to respond to more conservative measures may also require pharmacologic management, typically beginning with a selective serotonin reuptake inhibitor. This drug class seems to reduce emotional, cognitive-behavioral, and physical symptoms, and improve psychosocial functioning. Serotoninergic antidepressants such as fluoxetine, citalopram, sertraline, and clomipramine are effective when used intermittently during the luteal phase of the menstrual cycle. Treatment strategies specific to the luteal phase may reduce cost, long-term side effects, and risk of discontinuation syndrome. Patients who do not respond to a serotoninergic antidepressant may be treated with another selective serotonin reuptake inhibitor. Low-dose alprazolam, administered intermittently during the luteal phase, may be considered as a second-line treatment. A therapeutic trial with a gonadotropin-releasing hormone agonist or danazol may be considered when other treatments are ineffective. However, the risk of serious side effects and the cost of these medications limit their use to short periods.