Starting from the original studies of the 19th century, this review covers some of the advances achieved over the last 15 years since skin biopsy has become a diagnostic tool for neurologists. In a relatively short period of time, focused works demonstrated the correlation between the loss of intraepidermal nerve fibers (IENF) and symptoms and signs of small fiber neuropathy (SFN), and provided standardized protocols for nerve morphometry as well as normative reference values to be used in clinical practice. This contributed to the definition of the diagnostic criteria for SFN that is now recognized as a distinct nosologic entity. The relationship between IENF degeneration and neuropathic pain led to the recent discovery that SFN can be caused by mutations in sodium channels, providing evidence for a new diagnostic approach to the etiology of the disease in patients. The presence of myelinated nerve fibers in the dermis prompted studies focused on demyelinating neuropathies of genetic and immune-mediated origin. Specific changes in dermal myelinated nerves have been described suggesting a potential role for skin biopsy also in these fields. Finally, studies on the sequence of events occurring after nerve degeneration in experimental models and patients with chronic neuropathies allowed to understand better the ability of skin nerves to regenerate and the reasons for its failure, providing important hints for the use of skin biopsy as an outcome measure in clinical practice and neuroprotective trials.
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