Chronic activation of NMDA receptors by glutamate is toxic to cultured neurons. The extensive Ca2+ entry accompanying receptor activation is largely accumulated by the intracellular mitochondria, with resultant effects on mitochondrial membrane potential, ATP synthesis, glycolysis, reactive oxygen species generation and ultimately failure of cytoplasmic Ca2+ homeostasis and cell death. Each of these parameters is inter-related and in this review we describe attempts to separate out each factor to establish the sequence of events following NMDA-receptor activation. The conclusion is that mitochondrial Ca2+ accumulation is a key event in glutamate excitotoxicity, and that cells maintained by glycolysis in the absence of a mitochondrial membrane potential are highly resistant to glutamate excitotoxicity.