Skin biopsy for epidermal nerve fiber analysis provides an important objective test for the diagnosis of peripheral neuropathy, particularly small fiber sensory neuropathy (SFSN). The determination of epidermal nerve fiber density (ENFD) is reliable, with high diagnostic specificity and good sensitivity. Because of false negatives, biopsy results must be interpreted in conjunction with neurologic findings and laboratory results, including objective tests of sensory and autonomic function. SFSN most commonly is length dependent and is idiopathic in about half the patients. Biopsy of a proximal site (thigh) and a distal site (calf) typically shows greater abnormality of ENFD distally than proximally. More severe abnormality of ENFD in the thigh than in the calf raises the possibility of a non-length-dependent SFSN. The causes of this type of neuropathy, such as Sjögren's syndrome, sarcoidosis, and celiac disease, may be treatable.