Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice.