Around one of three diabetic patients is affected by distal symmetric polyneuropathy (DSP) which represents a major health problem, as it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity and increased mortality. Treatment is based on four cornerstones: (1) multifactorial intervention aimed at (near)normoglycaemia and reduction in cardiovascular risk factors, (2) treatment based on pathogenetic mechanisms, (3) symptomatic treatment, and (4) avoidance of risk factors and complications. Among the pathogenetic treatments only Ξ±-lipoic acid and epalrestat are available for treatment in several countries. Neuropathic pain, which is present in 8-26% of diabetic patients, exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life. Nonpharmacologic options such as nerve or muscle stimulation should always be given consideration. Among the centrally acting analgesic drugs for many years mainly the tricyclic antidepressants (TCA), carbamazepine, gabapentin, and opioids have been used to treat neuropathic pain. More recently, significant pain relief has been reported in clinical trials of painful diabetic neuropathy using agents such as the dual selective serotonin noradrenaline reuptake inhibitor (SNRI), duloxetine and the anticonvulsant pregabalin, a specific modulator of the Ξ± 2 Ξ΄ subunit of the voltage-dependent calcium channels. A promising new anticonvulsant is lacosamide. In future, drug combinations might also include those aimed at symptomatic pain relief and quality of life on one hand and improvement or slowing the progression of the underlying neuropathic process on the other hand.