Small-fiber neuropathy is a peripheral nerve disease that most commonly presents in middle-aged and older people, who develop burning pain in their feet. Although it can be caused by disorders of metabolism such as diabetes, chronic infections (such as with human immunodeficiency virus), genetic abnormalities, toxicity from various drugs, and autoimmune diseases, the cause often remains a mystery because standard electrophysiologic tests for nerve injury do not detect small-fiber function. Inadequate ability to test for and diagnose small-fiber neuropathies has impeded patient care and research, but new tools offer promise. Infrequently, the underlying cause of small-fiber dysfunction is identified and disease-modifying therapy can be instituted. More commonly, the treatments for small-fiber neuropathy involve symptomatic treatment of neuropathic pain.