Although there are a number of treatment modalities currently available for the treatment of cancer, mortality rates have only shown marginal improvement of late. Novel therapeutics, with decreased side effects, are desperately needed in order to improve the current prognosis for this deadly disease. To this end viruses with either natural or engineered tropism to tumors as well as immunotherapeutic approaches are being investigated as possible mono-therapies for the treatment of cancer. Each of these therapies have shown some successes on their own, however the combination of these two modalities may improve on the efficacy of the individual treatments. This chapter will focus on the use of oncolytic viruses in cancer therapy, the importance of the immune response, and its ability to further improve on the successes of oncolytic viral therapy.