Small-fiber sensory neuropathy with neuropathic pain had been a diagnostic challenge for neurologists. We and several groups have developed skin biopsy with quantitation of intraepidermal nerve fiber (IENF) density as a diagnostic approach. In the skin with small-fiber sensory neuropathy, there are pathological hallmarks: reduced IENF density with degeneration of subepidermal nerve plexuses and dermal nerves. Skin denervation is a major presentation of diabetic neuropathy and inflammatory neuropathies including Guillain-Barr syndrome and chronic inflammatory demyelinating polyneuropathy. The skin biopsy approach also provides an opportunity to examine dermal vasculature and inflammatory vasculopathy is demonstrated in vasculitic neuropathy, systemic lupus erythematosus, and eosinophilia-associated neuropathy. In addition to neuropahtologic evidence, the functional consequences of cutaneous nerve degeneration can be assessed with quantitative sensory testing (QST), contact heat evoked potential (CHEP), and functional magnetic resonance imaging (fMRI). One major etiology of small-fiber sensory neuropathy is familial amyloid polyneuropathy caused by mutations of transthyretin (TTR). We recently conducted studies on a large cohort of unique TTR mutation on Ala97Ser in Taiwan. These patients had significant skin denervation in addition to motor and autonomic neuropathy. Taken together, the skin biopsy with quantitation of IENF density provides diagnostic utility for small-fiber sensory neuropathy and the combination of psychophysical, physiological, and neuroimaging examinations offer comprehensive assessments for patients with neuropathic pain due o cutaneous nerve degeneration.