Patients struggling with diabetes are at elevated risks for several sight-threatening diseases, including proliferative diabetic retinopathy (DR). DR manifests in two stages: first, the retinal microvasculature is compromised and capillary degeneration occurs; subsequently, an over-compensatory angiogenic response is initiated. Early changes in the retinal microcirculation include disruptions in blood flow, thickening of basement membrane, eventual loss of mural cells, and the genesis of acellular capillaries. Endothelial apoptosis and capillary dropout lead to a hypoxic inner retina, alterations in growth factors, and upregulation of inflammatory mediators. With disease progression, pathologic angiogenesis generates abnormal preretinal microvessels. Current therapies, which include panretinal photocoagulation and vitrectomy, have remained unaltered for several decades. With several exciting preclinical advances, emergent technologies and innovative cellular targets may offer newfound hope for developing "next-generation" interventional or preventive clinical approaches that will significantly advance current standards of care and clinical outcomes.