On August 14, 1987, the Centers for Disease Control revised the surveillance case definition for the acquired immunodeficiency syndrome (AIDS) to include several indicator diseases. The addition of herpes simplex virus (HSV) infections to the definition reemphasized the increasing frequency of severe HSV infections in patients also infected with the human immunodeficiency virus (HIV). These infections in patients with AIDS are associated with considerable morbidity similar to reports of HSV in other immunocompromised populations. Their spectrum can include persistent or recurrent genital disease, severe visceral involvement, and disseminated infection. Patients with AIDS also are at increased risk of drug toxicities when receiving treatment for HSV infections in addition to antiretroviral therapy. Acyclovir, a selective and specific inhibitor of HSV replication, has been the mainstay of safe and effective treatment for HSV for more than a decade. However, reports of acyclovir-resistant strains of HSV in patients with AIDS have been steadily increasing since 1989. Although foscarnet has been successful in treating acyclovir-resistant strains, foscarnet-resistant strains have also been isolated. The search to find novel approaches for the treatment and suppression of HSV in patients with AIDS has become an added challenge in the management of this devastating disease.