Approximately one of three diabetic patients is affected by distal symmetric polyneuropathy, which represents a major health problem because it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity and increased mortality. Treatment is based on three cornerstones: 1) multifactorial intervention aimed at (near)-normoglycemia and reduction in cardiovascular risk factors; 2) treatment based on pathogenetic mechanisms; and 3) symptomatic treatment. Among the pathogenetic treatments, α-lipoic acid is the only available drug in several countries. Significant relief of neuropathic pain has recently been reported for duloxetine and pregabalin. Among at least 50 new drugs for treatment of neuropathic pain in the pipelines, there are several promising candidates such as lacosamide. Individual tolerability remains a major aspect in any treatment decision.