Hippocrates was the first to describe lesions that could have been caused by herpes simplex virus (HSV), but the clinical conditions caused by this virus have only been described in more detail over the past 3 centuries. Most of the key findings relating to HSV infection and treatment have been made since the early 20th Century. These range from discovering some of the mechanisms behind virus latency and reactivation, to the development of the drug aciclovir, which was the first selective inhibitor of HSV replication. This review provides an evolutionary understanding of HSV, but HSV research is still in its golden age. New facts continue to emerge about HSV, and manipulation of the virus is providing much information. Genetic engineering of this virus is likely to have a most significant impact on future medical therapies, which could extend to specialties beyond virology.