Programmed cell death is an essential process in the development of the central nervous system (CNS) and is fundamental for the control of the final number of neurons and glial cells. Excessive cell death has been implicated in a growing number of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis as well as ischemic injury. We review the contribution of death receptors of the tumor necrosis factor (TNF)/nerve growth factor (NGF) family to cell death and survival in the context of CNS pathology, indicating the possible value of manipulating cell death induced by these receptors for the treatment of CNS diseases and injury.