This chapter discusses painful diabetic peripheral neuropathy. This is a major cause for disability in those suffering from diabetes. The exact pathogenesis of diabetic neuropathy remains under investigation. It is known that poor glycemic control is associated with early development of neuropathy. The mainstay of treatment for diabetic neuropathy remains focused on symptomatic relief. First-line agents include tricyclic antidepressants (TCAs), used at lower dosing than traditionally used for antidepressant purposes. TCAs have effects at multiple sites as they inhibit the reuptake of serotonin and norepinephrine and act as antagonists at N-methyl-D-aspartate (NMDA) and alpha-adrenergic receptors. Interventional modalities for the treatment of painful diabetic neuropathy are still relatively new but have potentially promising results. These include transcutaneous electrical stimulation, acupuncture, sympathetic blockade and neurolysis, and dorsal column stimulation.