Approximately one in three people with diabetes is affected by diabetic distal symmetric sensorimotor polyneuropathy (DSPN), which represents a major health problem as it may present with excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality and impaired quality of life. Neuropathic pain causes considerable interference with sleep, daily activities, and enjoyment of life. Treatment is based on four cornerstones: (1) intensive diabetes therapy and multifactorial risk intervention; (2) treatment based on pathogenetic mechanisms; (3) symptomatic treatment; and (4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Management of chronic painful DSPN remains a challenge for the physician and should consider the following practical rules: the appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dosage based on efficacy and side effects; lack of efficacy should be judged only after 2-4 weeks of treatment using an adequate dosage. Analgesic combination therapy may be useful, and potential drug interactions have to be considered given the frequent polypharmacy in people with diabetes. Not only increased alcohol consumption but also the traditional cardiovascular risk factors such as visceral obesity, hypertension, hyperlipidemia and smoking have a role in the development and progression of diabetic neuropathy and hence need to be prevented or treated.