Clinical trials of oncolytic viruses (OVs) for cancers have revealed that these agents are well tolerated. However, clear-cut evidence of efficacy has been elusive. Although investigators are attempting to generate more efficacious OVs, a fundamental issue continues to limit the efficacy of cancer virotherapy-the response of the host to the ongoing viral infection. This response occurs at the level of intracellular tumor defenses to the viral infection, extracellular stromal reactions to the propagating virus, and, importantly, active host defenses consisting of innate immune as well as inflammatory angiogenic responses. The combination of these host responses severely limits and curtails tumor cell infection and viral replication, thus limiting anticancer efficacy. We believe that such host responses have to be circumvented, at least temporarily or partially, or both, in order to fulfill the promising anticancer effects of these agents.