Enormous interest in cell death in the past several years has moved apoptosis to the forefront of scientific research. Apoptosis has been found to mediate cell deletion in tissue homeostasis, embryological development, and immunological functioning. It also occurs in pathological conditions, including cancer and acquired immunodeficiency syndrome, and is implicated in neurodegenerative diseases. Claims of neuronal apoptosis induced by various agents and conditions are published regularly, but in many instances the data are questionable because they are incomplete. This review presents a brief history of apoptosis and describes the evidence required before claims of apoptosis are made. Summaries and critiques of important investigations concerning the genetic and biochemical regulation of neuronal apoptosis are presented, as are other studies describing connections between apoptosis and neuronal cell death in physiological and pathological situations. There is a realization that apoptosis can be programmed and is distinguishable from necrotic cell death. Combining apoptosis with programmed cell death produces misleading terminology and confusion over these two forms of cell degeneration. Further investigations into neuronal apoptosis should focus on all of the criteria that the original investigators outlined 25 years ago, to clarify whether apoptosis and/or another form of cell death mediates neuronal degeneration in physiological settings and in neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemia/stroke.