Ethel Nakakawa1, Steven J Reynolds21Makerere University College of Health Sciences, Department of Microbiology, Kampala, Uganda; 2Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD and Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Herpes simplex virus (HSV) type 1 and 2 are among the most common transmitted viral infections causing a spectrum of mucocutaneous and other syndromes. Treatment of these infections has primarily been with acyclovir (ACV) and prodrugs valacyclovir and famcyclovir. Immunocompromised hosts either due to human immunodeficiency virus (HIV) or other factors have given rise to an increase in ACV resistant viruses most commonly due to a mutation in the cellular thymidine kinase enzyme. This review focuses on the spectrum of disease caused by HSV 1 and 2, the emergence of ACV resistant disease, and the role of alternative agents including cidofovir in the treatment of ACV resistant disease.Keywords: herpes simplex virus, HIV, resistance, cidofovir