The ability of isolated brain mitochondria to accumulate, store and release calcium has been extensively characterized. Extrapolation to the intact neuron led to predictions that the in situ mitochondria would reversibly accumulate Ca²⁺ when the concentration of the cation in the vicinity of the mitochondria rose above the ‘set-point’ at which uptake and efflux were in balance, storing Ca²⁺ as a complex with phosphate, and slowly releasing the cation when plasma membrane ion pumps lowered the cytoplasmic free Ca²⁺. Excessive accumulation of the cation was predicted to lead to activation of the permeability transition, with catastrophic consequences for the neuron. Each of these predictions has been confirmed with intact neurons, and there is convincing evidence for the permeability transition in cellular Ca²⁺ overload associated with glutamate excitotoxicity and stroke, while the neurodegenerative disease in which possible defects in mitochondrial Ca²⁺ handling have been most intensively investigated is Huntington's Disease. In this brief review evidence that mitochondrial Ca²⁺ transport is relevant to neuronal survival in these conditions will be discussed.