Since its beginning in the early 1970s, the field of angiogenesis research has grown rapidly and it has now become apparent that the endothelial cell is a critical regulator of the malignant phenotype. Multiple antiangiogenic agents have now been used in the clinic yet a better understanding of the process of angiogenesis is still needed before these agents can be successfully incorporated into clinical practice. Although antiangiogenic agents offer great therapeutic potential, preclinical and clinical studies suggest that these agents will have a delayed onset of activity and may only induce disease stabilization for patients with advanced malignancy. The use of radiation therapy for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with antiangiogenic agents. Thus, the use of angiogenesis inhibitors in combination with radiation therapy should help to overcome the limitations of each leading to enhanced efficacy and diminished toxicity. The goal of this review is to provide an update of ongoing progress and current challenges related to the use of angiogenesis inhibitors with radiation therapy.