Diabetic retinopathy (DR) has been considered to be a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which may antedate, and also participates in, the microcirculatory abnormalities that occur in DR. Therefore, the study of the underlying mechanisms that lead to neurodegeneration will be essential for identifying new therapeutic targets in the early stages of DR. Elevated levels of glutamate, oxidative stress, the overexpression of the renin-angiotensin system and the upregulation of RAGE play an essential role in the retinal neurodegeneration induced by diabetes. Finally, the balance between the neurotoxic and neuroprotective factors is crucial in determining the survival of retinal neurons. In this review we will focus on neurotrophic factors already synthesized by the retina in physiological conditions as a new therapy strategy for neuroprotection.