Deprivation of sympathetic neurons of their physiological neurotrophic factor, nerve growth factor (NGF), leads to degeneration of soma and neurites, followed by loss of viability. The progression of degeneration and death are dependent upon macromolecular synthesis indicating an active participation of neuronal metabolism. Loss of viability begins only after a considerable delay after onset of NGF deprivation suggesting the presence of a sequence of degenerative events that triggers death. Such a sequence of degenerative events predicts that the activity of neuroprotective agents functioning by different mechanisms will be restricted to particular windows in time. The time-course of commitment to die as measured by the ability of NGF-deprived neurons to respond to NGF with long-term survival precedes the time-course of loss of viability by only a few hours, demonstrating that NGF displays neuroprotective properties for most of the time between onset of deprivation and death. Furthermore, NGF repairs and reverses the degenerative changes caused by prolonged periods of NGF deprivation. Because of these two aspects of NGF action, NGF demonstrates superior properties as a neuroprotective agents. NGF deprivation initiates DNA fragmentation of the neuronal genome into oligonucleosomal fragments in close temporal association with the onset of commitment to die. This is consistent with the idea that DNA fragmentation may be instrumental in causing the commitment to die. Thus, DNA fragmentation may serve as a marker of the physiologically most relevant critical step occurring during degeneration and may indicate the end of the period during which trophic factors are useful as neuroprotective agents. These results may be transferable to neurodegenerative diseases or sequelae of neuronal injury because of similarities in the phenomenology of degeneration and death.