The type of cell death encountered in neuronal cell cultures exposed to excitatory amino acids-such as glutamate, the major excitatory neurotransmitter in the central nervous system, or free radicals, such as nitric oxide (NO') and superoxide anoin (O2"'), which react to form peroxynitrite (ONOO')-appears to depend on the intensity of the exposure and may involve two temporarily distinct phases. Following relatively fulminant insults, an initial phase of necrosis -associated with extreme energy depletion -may simply reflect the failure of neurons to carry out the 'default' apoptotic death program used to efficiently dispose of aged or otherwise unwanted cells. Neurons recovering mitochondrial energy potential after an initial fulminant insult or following a more subtle inciting injury may subsequently undergo apoptosis, possibly associated with a factor released from mitochondria that triggers this death program. The maintenance of balanced energy production may be a decisive factor in detemining the degree, type, and progression of neuronal injury caused by 'excitotoxins' and free radicals. Similar events could possibly occur in vivo after ischemia or other insults.