The central nervous system (CNS) is a major dose-limiting organ in clinical radiotherapy (XRT). The underlying mechanisms of radiation-induced injury in this organ remain unclear. For many years, research has focused on identifying the major target cells of damage, and depletion of target cells due to reproductive or clonogenic cell death was believed to be the primary cause of tissue damage and organ failure. There is now an increasing body of data indicating that the response of the CNS after XRT is a continuous and interacting process. This review addresses some of the recent advances in our understanding of the mechanisms of CNS radiation damage. Specifically, the focus is on apoptotic cell death, and cell death and injury mediated by secondary damage. These potentially reversible components of the injury response provide important targets for neuroprotective interventions.