Neurodegeneration results in devastating illnesses with few effective treatments. Mitochondrial dysfunction has been associated with several neurodegenerative diseases. Neurons are highly energetic cells and rely heavily on healthy mitochondria. Much recent work has focused on the causes of mitochondrial dysfunction and resulting diseases. This chapter details how DNA damage results in mitochondrial dysfunction by nuclear to mitochondrial signaling or direct mitochondrial DNA damage. It also reviews current literature about neurodegenerative disease and its relationship to DNA damage and repair.