Diabetic retinopathy (DR), one of the leading causes of preventable blindness, has been considered 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 participates in the development of microvascular abnormalities. Therefore, the study of the underlying mechanisms leading to neurodegeneration and the identification of the mediators in the crosstalk between neurodegeneration and microangiopathy will be essential for the development of new therapeutic strategies. In this review, an updated discussion of the mechanisms involved in neurodegeneration, as well as the link between neurodegeneration and microangiopathy, is presented. Finally, the therapeutic implications and new perspectives based on identifying those patients with retinal neurodegeneration are given.