In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient’s own tumor into a nidus for presentation of tumor-specific antigens in a way that will stimulate and diversify an anti-tumor T cell response. Radiation therapy (RT) may serve as a method of in situ tumor vaccination. The mechanisms whereby RT interacts with tumor cells and the TME include: 1) temporary local eradication of RT-sensitive immune lineages including suppressor and effector lymphocytes; 2) local release of inflammatory cytokines and damage-associated molecular patterns resulting in local effects on endothelial cell expression of adhesion receptors, immune cell trafficking, and immune cell activation; 3) immunogenic tumor cell death and release of tumor-specific antigens; and 4) induction of phenotypic changes in the expression of immune susceptibility markers on tumor cells surviving RT. Consequently, RT enhances dendritic cell maturation, antigen cross-presentation, and diversification of anti-tumor T cell response. However, the capacity of external beam RT (EBRT) targeting one tumor to elicit a systemic anti-tumor immune response is limited. This occurs in part, from the local and systemic effects of immunosuppressive cells that pervade the TME in distant non-radiated tumors. Although EBRT may prime a more effective T cell response, when these effector T cells (Teff) circulate to non-radiated tumors they encounter a suppressive TME and poorly susceptible tumor cells. Furthermore, suppressive immune cells (e.g., regulatory T cell [Tregs]) in distant non-radiated metastatic tumors may circulate to the radiated tumor site after RT, and inhibit local priming of tumor reactive T cells. This reflects a need to further address the suppressive TME of distant tumors not targeted by EBRT. While it is not typically feasible to deliver EBRT to all sites of metastatic disease (due to immune suppression and inability to target microscopic disease), we can achieve this using molecular targeted radiotherapy (MTRT).