Oral acyclovir has been used successfully to treat and prevent symptomatic episodes of genital herpes simplex virus infection. Daily suppressive therapy has proven to be safe and effective when used continuously for periods as long as 4 years. Several new regimens have been shown to be effective and are likely to be more convenient for patients than previous schedules. In vitro resistance to acyclovir does not appear to be associated with clinical failure of treatment in immunocompetent hosts, but available data are limited and concerns remain. Failure of treatment in cases due to acyclovir-resistant strains has been reported in immunocompromised patients infected with the human immunodeficiency virus. The safety of acyclovir use by pregnant women has not been established. The value of acyclovir for the prevention of mucocutaneous ulcerations in asymptomatic persons or for the prevention of primary infections is unknown. Judicious use of acyclovir only by persons with clinically apparent infections is warranted at the present time.