Advances in molecular imaging have enabled the study of the nuances of disease and the subtlies of therapeutic responses. In cancer imaging has improved the study of immune cell therapies (1) and helped to reveal the nature of residual disease (2). These studies have contributed to the emerging paradigm of cancer stem cells, which suggests that the root of a cancer may be metabolically and phenotypically distinct from the bulk of the tumor (2). Therefore, therapeutic strategies with overlapping and redundant specificities covering the full range of the disease course need to be developed and applied to the treatment of cancer. The objective of such approaches is to target the tumor cells that persist after conventional therapies as these are the cells that result in relapse and subsequent morbidity and mortality. We have used imaging to refine the combination of an immunotherapy and an oncolytic viral therapy to capture the broad specificity of each and overcome their limitations (3). We combined cytokine induced killer (CIK) cells—an ex vivo expanded and systemically deliverable immune cell with tumoricial capabilities—with oncolytic vaccinia viruses that have been modified so that their replication is selective for tumor cells. The CIK cells serve as delivery vehicles to get the virus to the tumor and infected tumor cells then upregulate the cell surface markers that the CIK cells use to recognize and kill the tumor. As such the effects of the combination therapy are synergistic. We have demonstrated safety and efficacy of this dual biotherapy in a variety preclinical models of solid tumors and hematologic cancers. Individually each agent has been shown to be safe, with minimal toxicities, and to hold promise for the treatment of cancer and for further clinical development. The preclinical imaging and efficacy data indicated that the combination therapy results in increased anti-tumor effects relative to either therapy alone and does not require any additional steps in the preparation of either therapeutic agent. After elimination of tumor cells in immunocompetent animals using this approach a strong cytotoxic T cell response was observed in the treated animals and relapse of the tumor was not observed in many of these animals even after re-inoculation of these mice with new tumor cells. The study of complex diseases and combination therapies is greatly improved through the use of imaging approaches that are capable of cellular and molecular specificity in living animal models of human biology and disease.