Radiotherapy is widely used in the management of tumors of the central nervous system (CNS) primarily because these tumors, in general, remain localized and are usually not completely removed at surgery. Therefore, radiotherapy serves as a valuable adjunct. However, due to radiation resistance, survival for most patients with CNS tumors remains poor. Radiosensitizers are considered useful for CNS tumors because the majority of these tumors cause death due to local progression, thus emphasizing the significance of improving local control. In addition, these neoplasms consist of a rapidly growing cell population surrounded by slowly proliferating normal brain cells, thereby affording an opportunity for tumor-selectivity. Historically, several classes of radiation sensitizers, including S-phase halogenated pyrimidines, oxygen mimetics and others, have been tested without clear evidence of clinical benefit. Recently, two agents with very different mechanisms of action have gained attention and are currently in clinical trials; these agents, efaproxiral, a modulator of tumor hypoxia, and motexafin-gadolinium, a redox modulator, are the focus of this review.