Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved. These findings have implications for the optimization of oncolytic immunotherapy, at least that based on NDV, and further confirm that specific combinatorial approaches are promising for clinical development.