Herpes simplex virus (HSV) infections are very common in the general population and can be treated with the nucleoside analogue acyclovir. Acyclovir is initially phosphorylated intracellularly in HSV-infected cells by a viral-specific thymidine kinase to acyclovir-monophosphate. The monophosphate is subsequently di- and triphosphorylated by host cellular kinases to the active form of the drug, which inhibits HSV DNA polymerase and incorporates into the elongating viral DNA and causes chain termination. Acyclovir resistance has been increasingly described and is caused by mutations in either the thymidine kinase or the DNA polymerase genes. These mutations result in decreased or absent HSV thymidine kinase production, altered affinity of the thymidine kinase for acyclovir-triphosphate, or altered affinity of the HSV DNA polymerase for acyclovir-triphosphate. Thymidine kinase deficiency accounts for approximately 95% of acyclovir-resistant isolates. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patients and is usually characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus. Several large surveys have been done in an effort to determine the incidence of in vitro and clinical acyclovir resistance. Among immunocompetent hosts, even those who have received > or = 6 years of continuous acyclovir, the prevalence of acyclovir-resistant isolates has remained stable at approximately 3%. Only three cases of clinical resistance of HSV to acyclovir have been reported. However, the incidence in immunocompromised patients, particularly those with AIDS and those who have had bone marrow transplants, is increasing. Transmission of acyclovir-resistant isolates from person to person has not been documented, but due to the increased use of acyclovir and newer drugs, such as famciclovir, there is great concern that this transmission might occur in the future. Continued surveillance in both immunocompetent and immunocompromised hosts for the development of clinical acyclovir-resistant HSV disease is necessary.