This is a new, exciting time for the study of peripheral nerve and its diseases. For many years research in peripheral neuropathies largely involved descriptive analysis, a situation which is now rapidly giving way to hypothesis testing with the development and validation of molecular genetic tools. Although it has been known for some time that many neuropathies target the most distal portions of the longest peripheral nerves, a process variously referred to as central-peripheral distal neuropathy, “dying-back” neuropathy, or “stocking-glove” neuropathy, proposed mechanisms driving axon loss have been generally unproven/untestable. Studies have shown that mitochondrial DNA mutations accumulate in distal axons and a unifying theory of distal neuropathy has been proposed based on underlying mitochondrial aging defects in mitogenesis and, thus, distal axon susceptibility, particularly if axonal transport defects also accompanied them. Increased levels of mtDNA mutations have been described in some painful neuropathies (e.g., HIV) compared to baseline HIV patients and controls. For some time no therapies were available to preserve and prevent the development of peripheral neuropathy and, with a variety of expected pathogenetic mechanisms, complex cocktails of therapeutic agents were envisioned. Although structure and ultrastructure continue to be relevant in the studies of mitochondriopathy-driven neuropathies, more techniques have been added and more complex hypotheses now expand the concept and focus directly on mitochondrial pathology or dysfunction. It is now possible to definitively test possible pathogenetic mechanisms with a variety of new tools and to formulate new and testable hypotheses.