Mutations in mitochondrial DNA cause a number of neurological diseases with defined neuropathology; however, mutations in this genome have also been found to be important in a number of more common neurodegenerative diseases. In this review, the authors discuss the importance of mitochondrial DNA mutations in a number of different diseases and speculate how such mutations could lead to cell loss. Increasing our understanding of how mitochondrial DNA mutations affect mitochondrial metabolism and subsequently result in neurodegenerative disease will prove vital to the development of targeted therapies and treatments.