Viruses have been engineered for cancer therapy in a variety of ways. Approaches include non-replicating gene therapy vectors, cancer vaccines and oncolytic viruses, but the clinical efficacy of these approaches has been limited by multiple factors. However, a new therapeutic class of oncolytic poxviruses has recently been developed that combines targeted and armed approaches for treating cancer. Initial preclinical and clinical results show that products from this therapeutic class can systemically target cancers in a highly selective and potent fashion using a multi-pronged mechanism of action.