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OBJECTIVE Microangiopathy is a major cause in diabetic polyneuropathy (DPN). This review examines evidence from both human and animal studies to elucidate the important microvascular factors in DPN. MATERIALS AND METHODS This is a literature review of articles published on PubMed in English. RESULTS There is an abundance of evidence linking endoneurial microvascular abnormalities to peripheral nerve dysfunction and pathology in patients with diabetes. These structural changes result in an abnormal diffusion barrier leading to endoneurial hypoxia. Furthermore, the functional changes of endoneurial microvessels characterized by reduced vasodilation and potentiated vasoconstriction also exacerbate the endoneurial hypoxia. Although reduced endoneurial blood flow has also been widely reported in established DPN, there is some evidence that blood flow may be elevated early in the course of the disease. Capillary dysfunction in DPN, which reduces the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow, may explain that the tissue may be hypoxic even in the context of normal or elevated nerve blood flow. The pathogenesis of painful DPN also remains unclear although neural hemodynamic changes have been demonstrated both in the peripheral and central nervous system, offering potential new insights for the treatments of this distressing condition. CONCLUSIONS Compelling experimental and human work has highlighted the close association connection between endoneurial microangiopathy and diabetic polyneuropathy. Future investigations will need to investigate the role of microvascular factors both in the periphery and the central nervous system in the pathogenesis of painful DPN.