Oncolytic viruses have been considered as a potential form of cancer treatment throughout the last century because of their ability to lyse and destroy tumor cells both in tissue culture and in animal models of cancer. However, it is only during the past decade that new molecular technologies have become available and understanding of genetic and molecular components of these viruses has increased to the point that they can be manipulated and made safe for use in treatment in humans. Thus there has been a revival of the concepts of conditionally replication-competent viruses and suicide gene therapy to supplement currently existing cancer therapies. While a wide variety of viruses have been closely studied for this purpose, herpes simplex virus type-1 (HSV-1) has received particularly close attention. The inherent cytotoxicity of this virus, if harnessed and made to be selective in the context of a tumor microenvironment, makes this an ideal candidate for further development. Furthermore, its large genome size, ability to infect cells with a high degree of efficiency, and the presence of an inherent viral-specific thymidine kinase gene add to its potential capabilities. This review explores work performed in this field and its potential for application in the treatment of cancers in humans.