Talimogene laherparepvec (T-Vec) is the first live virus to be approved by the US Food and Drug Administration for the treatment of cancer. This engineered version of herpes simplex virus type 1 (HSV-1) is the product of decades of preclinical work aimed at identifying and modifying aspects of the viral genome involved in virulence and immunogenicity. T-Vec preferentially infects and lyses tumor cells and, in some cases, induces a systemic immune response against the tumor. These properties have translated into significant and durable clinical responses, particularly in advanced melanoma. Many unanswered questions remain, including how to augment these clinical responses and which other tumor types may respond to oncolytic therapy. Here, we review the development of T-Vec, our current understanding of its impact on the tumor immune micro-environment, and its safety and efficacy in clinical trials for melanoma and other cancers.