BACKGROUND Talimogene laherparepvec (T-VEC) is the first oncolytic virus therapy approved by the United States Food and Drug Administration (in 2015) for the treatment of advanced-stage melanoma. Despite a paucity of Phase III trials for T-VEC as a therapy for non-melanoma cancers, successful off-label use of T-VEC for this purpose has been reported in the literature. OBJECTIVE We sought to review the literature describing T-VEC as a treatment for non-melanoma cancer. METHODS Systematic searches of the PubMed literature database and ClinicalTrials.gov website were performed in July 2020, focusing on T-VEC in combination with non-melanoma cancer, including squamous cell carcinoma, Merkel cell carcinoma, sarcoma, cutaneous B-cell lymphoma, and cutaneous T-cell lymphoma. Articles were screened based on their title and abstract. RESULTS Nine articles with 87 patients were included. Relevant articles included case reports, case series, and Phase I and Phase II trials. The majority of patients in the studies had refractory cancers or had been heavily pretreated. Overall, T-VEC demonstrated efficacy for non-melanoma cancer, both independently and in combination with biologics. CONCLUSIONS T-VEC has demonstrated efficacy for non-melanoma cancers. Phase III trials of T-VEC for this indication are warranted to expand its clinical utility.