Oncolytic virotherapy is an evolving but, as yet, unrealized treatment option for cancer. This approach harnesses the cancer-restricted replicative activity of engineered viruses to achieve tumor cell kill. Tumors that are resistant to chemotherapy or radiotherapy can be susceptible to viral oncolysis because of distinct cell kill mechanisms. There is now compelling evidence that collateral induction of anti-tumor immune responses contributes substantially to viral antitumor activities. In addition to the expected anti-viral immune clearance, the "danger" signal created by virus-infected cells can generate immune co-stimulation known to override immune suppression and reverse tolerance within the tumor microenvironment. Our recent findings indicate that immune activation augments the clinical outcomes of oncolytic virotherapy. Strikingly similar and robust clinical response rates ( > 25%) were observed among advanced cancer patients following intratumoral treatments with adenoviral (AdΔ24) and herpes simplex (JS1/34.5-/47) constructs armed with an integrated granulocyte-macrophage colony-stimulating factor (GMCSF) payload. Both agents produced regressions in injected as well as distant, uninjected lesions, demonstrating systemic effectiveness. We discuss the innate and adaptive immune activating events that may contribute to these clinical outcomes, and examine systemic delivery strategies to tilt the immunological balance from viral clearance to tumor elimination.