Painful peripheral neuropathy is a common complication of diabetes mellitus that can affect almost every tissue of the body. In the absence of a curative therapy for this disorder, pharmacologic or nonpharmacologic tools, or a combination of both, can be used to provide relief of symptoms. This article reviews medications currently used to manage painful diabetic neuropathy. The pathogenesis of painful diabetic neuropathy is described as a basis for understanding medication selection. The literature describing the pharmacologic properties of medications used to treat painful diabetic neuropathy is also reviewed. Comparisons of medication dosages, frequencies, and adverse effects are offered to help with selection of the most appropriate agent for each individual patient. (J Am Podiatr Med Assoc 97(5): 394–401, 2007)