A series of randomized, placebo-controlled, double-blind clinical trials conducted from 1980 to the present provide the basis for appropriate management of varicella-zoster virus (VZV) infections. Placebo recipients in these studies have also provided valuable natural history data on the clinical course of VZV infections. The protocols in toto have shown acyclovir (ACV) to be safe and effective for treatment of nearly all forms of acute VZV infection. A number of issues still need to be addressed, including appropriate dosage, importance of early initiation of therapy, cost-benefit ratio, and viral resistance. Considering the data in aggregate, the author recommends ACV treatment for all acute VZV infections in immunocompromised hosts; for acute herpes zoster infections in all adults; and for varicella in otherwise healthy adults and adolescents, and children who contract it from a sibling.