Diabetic sensorimotor polyneuropathy (DSP) is a condition that has escaped direct management at the present time. The diagnosis of painful DSP (PDSP) is based upon important historical and clinical examination aspects, with some diagnostic assistance provided by nerve conduction studies. There is great complexity in the pathophysiology of DSP. Hyperglycemia in both humans and in animal axonal models appears to drive several metabolic pathways contributing to initiation and progression in humans and to the presence of peripheral neuropathy in animal models. Pharmacological treatment is required in a majority of patients with PDSP. Most guidelines suggest that anticonvulsants and antidepressants be used first, prior to opioids due to the risk of dependency, tolerance, dose escalation, and diverse effects. Future treatments may include better methods to modulate loss of central inhibition, better topical applications, and directed therapy against neuroinflammatory changes of microgliosis and astrogliosis.