Herpes simplex viruses (HSVs) have entered clinical trials as oncolytic agents. The following properties make them good candidates. It is a mild pathogen; drugs (Aciclovir) are available to control viral infection; the large genome is amenable to genetic engineering, they can be rendered cancer-specific by deletion of genes, envelope glycoproteins allow the insertion of heterologous ligands to achieve modification of the natural tropism. Genetically modified HSVs have been thoroughly tested in humans. New generation recombinants retargeted to cancer-specific heterologous receptors have been generated and are presently evaluated in pre-clinical settings. They will be reviewed along with the molecular bases of cancer specificity and the strategies for the enhancement of oncolytic potential of HSV recombinants.