Motexafin gadolinium is a novel, MRI-detectable, an 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. Motexafin gadolinium catalyzes the oxidation of intracellular reducing metabolites such as ascorbate, glutathione, nicotinamide adenine dinucleotide phosphate, and protein thiols, generating reactive oxygen species in a process known as futile redox cycling. The depletion (through oxidation) of these reducing metabolites removes the substrate necessary in a cell to repair oxidative damage induced by radiation and, left unrepaired, such radiation-induced oxidative DNA damage is converted into lethal double-stranded breaks. Motexafin gadolinium has tumor-specific uptake, normal tissue sparing, and tolerable and reversible toxicities in clinical trials. Motexafin gadolinium 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 Non-small-cell lung carcinoma. Motexafin gadolinium use in conjunction with radiosurgery and whole brain radiation therapy in the setting of brain metastases is currently being studied, as is Motexafin gadolinium with radiation and temozolomide in patients with glioblastoma multiforme.