Herpes simplex viruses types 1 (HSV-1) and 2 (HSV-2) are associated with a wide range of diseases related to infection of epithelial or neuronal tissues. The two viruses evidence distinct pathogenesis aspects, which are likely mediated by distinct viral genes. One such gene is UL39, which codes for the large subunit of ribonucleotide reductase (R1, also known as ICP6 and ICP10 for HSV-1 and HSV-2 respectively). The HSV-2 R1 has serine-threonine protein kinase (PK) activity, which is located within the first 411 amino acids (ICP10PK). ICP10PK is a constitutively activated growth factor receptor (GFR) that signals through the Ras/MEK/ERK pathway. It has transforming activity in immortalized cells, mitogenic (but not transforming) activity in normal diploid cells, and anti-apoptotic (survival) activity in post mitotic neurons in the central nervous system (CNS). In addition to the Ras/MEK/ERK, ICP10PK also activates the PI3-K/Akt pathway, upregulates the Ras family member Rap-1 and adenylate cyclase and activates the B-Raf kinase activity. ICP10 PK appears to have a cellular origin. Its conservation is most likely to reflect the ability to impart an evolutionary advantage, particularly in the face of pro-apoptotic viral genes. Indeed, activation of the Ras/MEK/ERK pathway by ICP10PK is required for virus growth.