Autonomic neuropathy is a significant complication of diabetes resulting in increased patient morbidity and mortality. A number of studies, which have shown correspondence between neuropathologic findings in experimental animals and human subjects, have demonstrated that axonal and dendritic pathology in sympathetic ganglia in the absence of significant neuron loss represents a neuropathologic hallmark of diabetic autonomic neuropathy. A recurring theme in sympathetic ganglia, as well as in the pot-ganglionic autonomic innervation of various end organs, is the involvement of distal portions of axons and nerve terminals by degenerative or dystrophic changes. In both animals and humans, there is a surprising selectivity of the diabetic process for subpopulations of autonomic ganglia, nerve terminals within sympathetic ganglia and end organs, from end organ to end organ, and between vascular and other targets within individual end organs. Although the involvement or autonomic axons in somatic nerves may reflect an ischemic pathogenesis, the selectivity of the diabetic process confounds simple global explanations of diabetic autonomic neuropathy as the result of diminished blood flow with resultant tissue hypoxia. A single unifying pathogenetic hypothesis has not yet emerged from clinical and experimental animal studies, and it is likely that diabetic autonomic neuropathy will be shown to have multiple causative mechanisms, which will interact to result in the variety of presentations of autonomic injury in diabetes. Some of these mechanisms will be shared with aging changes in the autonomic nervous system. The role of various neurotrophic substances and the polyol pathway in the pathogenesis and treatment of diabetic neuropathy likely represents a two-edged sword with both salutary and exacerbating effects. The basic neurobiologic process underlying the diabetes-induced development of neuroaxonal dystrophy, synaptic dysplasia, defective axonal regeneration, and alterations in neurotrophic substance may be mechanistically related.