Patients with complaints of numbness, tingling, and dysesthesias in the toes and feet are frequently referred to neurologists. Often, the only objective evidence for peripheral nerve dysfunction in these patients is limited to small-caliber sensory nerve fibers. On examination these patients may have reduced distal pinprick sensation, and distal leg skin biopsies show loss of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers have led to a growing impression that neuropathy can be associated with early diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the presenting symptom of either diabetes or IGT. Furthermore, the oral glucose tolerance test appears to be a more sensitive measure of glucose dysmetabolism in these patients than levels of fasting blood glucose or glycated hemoglobin. Patients with IGT-associated neuropathy may represent an attractive target population for future regenerative studies given that their neuropathy is less severe and presumably more easily reversed than neuropathy occurring in patients with diabetes.Historically, small-caliber fibers have not been extensively evaluated due to a lack of objective measures. Several measures to evaluate these fibers are emerging, including skin biopsy with visualization of epidermal nerve fibers. The accessibility of epidermal nerve fibers makes them an attractive target for nerve injury models, which have potential for development as novel outcome measures. Such approaches may address some of the challenges of past diabetic polyneuropathy trials.