The field of oncolytic virus therapy, the use of live, replicating viruses for the treatment of cancer, has expanded rapidly over the past decade. Preclinical models have clearly demonstrated anticancer activity against a number of different cancer types. Several agents have entered clinical trials and promising results have led to late stage clinical development for some viruses. The early clinical trials have demonstrated that oncolytic viruses by themselves have potential to result in tumor regression. Engineering of viruses to express novel genes have also led to the use of these vectors as a novel form of gene therapy. As a result, interest in oncolytic virus therapy has gained traction. The following review will focus on the first wave of clinical translation of oncolytic virus therapy, what has been learned so far, and potential challenges ahead for advancing the field.