Excitotoxicity and mitochondrial impairment have been implicated in the pathogenesis of both Huntington's disease (HD) and Parkinson's disease (PD). These two pathogenic processes are intertwined mechanistically. Mitochondrial dysfunction with ATP depletion impairs the activity of the Na+/K+-ATPase that maintains neuronal membrane potential. As a result, the voltage-dependent blockade by Mg++ of the N-methyl-D-aspartate (NMDA) class of glutamate receptor is reduced. In this setting, low concentrations of extracellular glutamate may become lethal. Additionally, mitochondrial impairment severely disrupts intracellular calcium homeostasis. Thus, mitochondrial dysfunction can produce secondary excitotoxicity. Mitochondria are also targets of excitotoxicity, such that NMDA receptor activation leads to mitochondrial swelling and generation of reactive oxygen species. Mitochondria isolated from HD patients have a reduced capacity to accumulate calcium; with graded calcium loads, they depolarize more readily and recover less well than control mitochondria. Normal mitochondria can be induced to behave like HD mitochondria by incubating them with polyglutamine-containing proteins similar to the mutant huntingtin protein that causes HD. In PD, a selective defect in mitochondrial complex I appears to be important in many cases. As the nigral dopamine neurons die, another group of neurons in the subthalamic nucleus become overactive. These subthalamic neurons are glutamatergic and project back to the dysfunctional dopamine neurons. It has been hypothesized that this increased glutamatergic drive upon already impaired neurons contributes to disease progression. Using a rat model of PD, we have found that chronic infusion of an NMDA antagonist into the subthalamic nucleus reduces degeneration of nigral dopamine neurons by more than 50%. Thus, mitochondrial defects and excitotoxicity appear to play important roles in HD and PD. Therapeutic strategies targeting these processes are likely to provide neuroprotection and slow disease progression.