Background: Diabetes mellitus is a chronic degenerative disease responsible for hyperglycemic episodes through insulin secretion deficiency or cellular resistance. Clinical diagnosis in diabetic patients established that this disease affects the CNS, damaging the brain and impairing cognition, thus establishing a clinical diabetic condition named diabetic encephalopathy. Despite the fact that physiological mechanisms responsible for the development of diabetic encephalopathy are still unclear, an excessive formation of reactive oxygen species, an alteration of acetylcholinesterase activity and a reduction of growth factor levels may be related with the pathogenesis of this condition. Pharmacological treatments with natural compounds have been proven to be useful in the treatment of a wide variety of diseases through their antioxidant actions.Methods: This study built a compendium of chemical compounds used for the treatment of diabetic encephalopathy demonstrating the most important physiological targets that future drugs should aim for. Results: As previously suspected, antioxidants and acetylcholinesterase inhibitors were useful to prevent memory loss in streptozotocin-induced animals. In addition, growth factors showed an improvement of memory in diabetic rodents. Most of the studies focused on antioxidant compounds despite cross studies researching both antioxidants and acetylcholinesterase activities. Conclusion: Therefore, it could be suggested that future studies regarding treatments for diabetic encephalopathy should focus on the antioxidant profile and acetylcholinesterase, since they seem to play pivotal roles in cognitive impairment in diabetes. No less important, studies with growth factors are also important physiological targets for treatment of diabetic encephalopathy.