Due to the remarkable ability to target and kill tumor cells, genetically engineering HSV-1 has been widely studied for its potency in cancer treatment. Several oncolytic herpes simplex viruses had been proved to be clinically effective in different phases of clinical trials against multiple cancers, which can also induce good antitumor immunity. In 2015,Amgen′s T-VEC has been approved by FDA for the treatment of melanoma. The combination with the conventional therapies, such as radiotherapy and chemotherapy, can further enhance the efficacy of virotherapy. Moreover, Immune checkpoint blockade therapy has been proved to be a promising strategy to fight multiple cancers, the combination of immune activation using oncolytic viruses and immune checkpoint inhibitors is likely to usher in a new era of cancer treatment.