Although there is clear evidence from experimental diabetic neuropathy (DN) models that the multiple pathways involved in neuronal degeneration cause overproduction of reactive oxygen species, oxidative stress, and cellular dysfunction, therapeutic approaches addressing these mechanisms have not yet provided a basis for a successful treatment of patients with DN. This review discusses the current knowledge on the pathomechanisms of unchecked reactive oxygen species accumulation, implications for specific treatment, and the need for carefully designed experimental studies and clinical trials closing the gap between promising results in experimental DN and its implementation into a pathogenetically oriented treatment.