Efforts to improve on cancer therapy have begun to capitalize on recent advances in our understanding of tumorigenesis. Tumor-specific characteristics are being exploited to develop selective antibodies and pharmacological inhibitors that specifically target cancer cells, and these agents are already showing clinical promise. None of these approaches, however, has captured our imagination as much as the use of replication-competent viruses to kill cancer cells. Whereas normal cells resist replication, tumor cells have an impaired antiviral response that sensitizes them to oncolytic viruses. One such virus is reovirus, a benign, naturally occurring virus that can effect tumor regression in animal models. Reovirus is demonstrating much promise in pre-clinical studies of cancer therapy and in clinical trials, where a lack of toxicity and signs of efficacy are generating excitement for this novel potential cancer therapeutic.