After more than a decade of intensive research and development efforts, the translation of promising viral-based gene therapies from the research lab to the clinic is both promising and unexpectedly challenging. Many of the same properties that make viral vectors attractive candidates to deliver genes for therapeutic purposes also impede the path to successful clinical development. Vectors for clinical use must be manufactured in relatively high yields such that hundreds of thousands or even millions of “doses” can be generated in a safe and cost-effective manner. Moreover, the resulting vector must exhibit genetic as well as structural stability, withstand storage at various temperatures for up to several years, and cause little or no toxicity in animals, and ultimately in humans. Herpes simplex viruses (HSV), while widespread in nature, have not been tested in human clinical studies as often as several other commonly used vectors, such as adenovirus, adeno-associated viruses (AAV), and retroviruses. In many ways however, HSV is emerging as a viable therapeutic platform and several clinical studies are either ongoing or planned for the very near future. The reason for this increased focus on HSV is due in part attributable to the unique properties that make HSV a stable and potentially potent vector for controlled gene delivery. In addition, the increasing experience with replication-competent vectors in human clinical studies has made it more familiar with clinicians. Therapeutic HSV can be characterized as replication-competent or replication-defective.