Diabetic retinopathy (DR) is a challenging public health problem mainly because of its growing prevalence and risk of blindness. In general, our current knowledge and practice have failed to prevent the onset or progression of DR to sight-threatening complications. While there are treatment options for sight-threatening complications of DR, it is crucial to pay more attention to the early stages of DR to decrease its prevalence. Growing evidence suggests many pathologic changes occur before clinical presentations of DR in euglycemic hyperinsulinemia, prediabetes, and diabetes. These pathological changes occur in retinal neurons, glia, and microvasculature. A new focus on these preclinical pathologies – especially on hyperinsulinemia – may provide further insight into disease mechanisms, endpoints for clinical trials, and druggable targets in early disease. Here, we review the current evidence on the pathophysiological changes reported in preclinical DR and appraise preventive and treatment options for DR.The Author(s). Published by S. Karger AG, Basel.