Motexafin gadolinium (MGd) is a novel, MRI-detectable, anticancer agent that enhances the cytotoxic potential of radiation therapy through several mechanisms, including depleting intracellular reducing metabolites that are necessary for repairing the oxidative damage induced by irradiation. It has tumor-specific uptake, normal tissue sparing, and tolerable and reversible toxicities in clinical trials. MGd's use in conjunction with whole-brain radiation therapy (WBRT) has demonstrated an improvement in neurocognitive decline, neurologic progression, and quality of life in patients with brain metastases from NSCLC. Its use in conjunction with radiosurgery and whole brain radiation therapy in the setting of brain metastases is currently being studied, as is MGd with radiation and temozolomide in patients with glioblastoma multiforme. MGd is also being actively investigated as a single agent or in combination with chemotherapy or radiation therapy in other tumors, including pediatric brain tumors, NSCLC, lymphoma, renal cell carcinoma, and pancreatic and biliary tumors.