Neurodegenerative disease such as Alzheimer's, Parkinson and Huntington's are all characterized by dysfunctional neurons and loss of cognitive/motor functions. Interestingly these three diseases involve overproduction, aggregation or abnormal degradation of a specific aberrant protein, which participates in disease pathogenesis. The aggregated proteins may induce disease causing pathways such as high oxidative stress and reduced neuronal metabolism. Several mechanisms are being considered as disease-causing and there is established and growing evidence that a breakdown in neuronal energy production may be an underlying cause in these diseases. The specific risk factors and molecular drivers for each disease vary, yet there are common defective bioenergetics pathways, which may drive neuronal dysfunction. While it has been appreciated that energy deficits can drive neuronal dysfunction and disease, it has for the most part been overlooked as a target pathway for designing novel disease modifying therapeutics. This editorial reviews selected evidence supporting energy deficits as disease-causing and proposes targets for design of new therapeutics.