A variety of mitochondrial DNA (mtDNA) defects, ranging from point mutations and large-scale deletions to severe reduction in the overall quantity of mtDNA (mtDNA depletion), may be associated with neuromuscular disorders. The nuclear genome, which encodes most of the proteins involved in mitochondrial biogenesis (regulation of maintenance, replication, and transcription of mtDNA), appears to be implicated in many of the mtDNA defects. In this review, we describe some of the mtDNA defects discovered by our laboratory and others in patients with neurologic disorders and analyze their potential relationship with the pathways and mechanisms involved in mitochondrial biogenesis.