Ionizing radiation has been employed in targeted cancer treatments for more than a century because of its cytotoxic effects on cancer cells. However, the responsiveness to radiation and the behavior of tumors in vivo may differ dramatically from observed behaviors of isolated cancer cells in vitro. While not fully understood, these discrepancies are due to a complex constellation of extracellular and intercellular factors that are together termed the tumor microenvironment. Radiation may alter or affect the components of the adjacent tumor microenvironment in significant ways, often with consequences for cancer cells beyond the direct effects of the radiation itself. Moreover, different microenvironmental states, whether induced or at baseline, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. This chapter describes this bidirectional relationship in detail, exploring the role and clinical implications of the tumor microenvironment with respect to therapeutic irradiation.