Herpes simplex viruses (HSVs) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy, HSV infections remain a significant worldwide public health problem. Vaccines offer the best hope for controlling spread and limiting HSV disease. This article discusses the pathogenesis and immunobiology of mucocutaneous HSV infections, summarizes the spectrum of diseases caused by HSV, and provides a review of the field of HSV vaccine research. This article also discusses what might be realistically expected of a vaccine intended for control of genital herpes and explores the question of whether a vaccine that is effective in controlling genital HSV disease might also be effective in controlling nongenital HSV disease. The efficacy of such vaccines for the full spectrum of HSV disease will eventually determine the timing and targeting of immunization, ranging from selective immunization in preadolescence to universal childhood immunization as part of the routine childhood regimen.