This review discusses the role of abnormal neurofilament (NF) expression, processing, and structure as an etiological factor in diabetic neuropathy. Diabetic sensory and autonomic neuropathy in humans is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demylelination, and loss of myelinated fibers-the latter is probably the result of a dying-back of distal axons. NF filaments are composed of three subunit proteins, NFL, NFM, and NFH, and are major constituents of the axonal cylinder. It is clear that any abnormality in synthesis, delivery, or processing of these critical proteins could lead to severe impairments in axon structure and function. This article describes mechanisms of synthesis, phosphorylation, and delivery of NF and discusses how these processes may be abnormal in diabetes. The pathological alterations in the ganglion and peripheral nerve that occur in sensory and autonomic neuropathy will be outlined and related to possible abnormal processing of NF. A major focus is the role of abberant NF phosphorylation and its possible involvement in the impaired delivery of NF to the distal axon. Identification of stress-activated protein kinases (SAPKs) as NF kinases is discussed in detail and it is proposed that hyperglycemia-induced activation of SAPKs may be a primary etiological event in diabetic neuropathy.