Several antiviral agents against herpes simplex virus (HSV) infection have been clinically studied. Earlier therapies include gluteraldehyde, povidone-iodine, butylated hydroxytoluene and ether. Nucleoside analogs have been tested for efficacy in HSV. Although acyclovir and adenine arabinoside have shown minimal therapeutic benefit, cidofovir has been successful in the treatment of acyclovir-resistant strains of HSV, and idoxuridine 15% in dimethyl sulfoxide, edoxudine and penciclovir have significant clinical benefit against HSV. Interferon-alpha has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine, dimethyl sulfoxide and nonoxynol-9, and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or further exploring combination therapy may result in efficacious treatment of HSV. Vaccination or gene therapy may also prove beneficial in future studies.