Mitochondria are essential organelles playing a central role in metabolism, calcium signaling, protein quality control and apoptosis. Neurons are highly dependent on mitochondria, and since they are postmitotic cells with complex shapes, it is a major challenge to distribute and maintain healthy mitochondria in their arbors. Not surprisingly, any type of mitochondrial defect in neurons contributes to neurodegeneration. Primary mitochondrial diseases are a clinically heterogeneous group of genetic disorders caused by mutations in either mitochondrial DNA (mtDNA) genes or nuclear DNA (nDNA) genes encoding for resident mitochondrial proteins. These disorders can occur at any age and can shut down any organ or tissue that is highly dependent on aerobic metabolism. They usually affect multiple systems and lead to neurological and myopathic features. In this chapter, we focus specifically on primary mitochondrial disorders that are clinically associated with neurodegeneration of the spinocerebellar tract, retina, or peripheral nerves. In these diseases, the proteins encoded by the respective mutated genes affect OXPHOS (Frataxin, COQ8A, mt-ND4, mt-ND6, mt-ND1, DNAJC30), mitochondrial protein quality control (Paraplegin, AFG3L2, PITRM1), or mitochondrial fusion and fission (OPA1, Mitofusin 2, GDAP1). The major cellular or animal models for this subset of rare diseases are described, with their limitations and advantages as well as preclinical therapeutic interventions. Models for the most common neurodegenerative diseases in which mitochondria play a role in pathogenesis but whose causative gene does not encode a mitochondrial protein are not included in this chapter.