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Energy failure from mitochondrial dysfunction is proposed to be a central mechanism leading to neuronal death in a range of neurodegenerative diseases. However, energy failure has never been directly demonstrated in affected neurons in these diseases, nor has it been proved to produce degeneration in disease models. Therefore, despite considerable indirect evidence, it is not known whether energy failure truly occurs in susceptible neurons, and whether this failure is responsible for their death. This limited understanding results primarily from a lack of sensitivity and resolution of available tools and assays and the inherent limitations of in vitro model systems. Major advances in these methodologies and approaches should greatly enhance our understanding of the relationship between energy failure, neuronal dysfunction, and death, and help us to determine whether boosting bioenergetic function would be an effective therapeutic approach. Here we review the current evidence that energy failure occurs in and contributes to neurodegenerative disease, and consider new approaches that may allow us to better address this central issue. Ann Neurol 2013;74:506–516