Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of diabetic complications, including diabetic retinopathy (DR). This review article provides an overview of the results of clinical trials evaluating the potential benefits of lipid-lowering drugs, such as fibrates, omega-3 fatty acids, and statins, for the prevention and treatment of DR. Although several clinical trials demonstrated that treatment with fibrates leads to improvement of DR, there is a dissociation between the protective effects of fibrates in the retina, and the intended blood lipid classes, including plasma triglycerides, total cholesterol, or HDL:LDL cholesterol ratio. Guided by these findings, plasma lipid and lipoprotein-independent mechanisms are addressed based on clinical, cell culture, and animal model studies. Potential retinal-specific effects of fatty acid oxidation products, cholesterol, and ceramide, as well as lipid-independent effects of PPAR alpha activation, are summarized based on the current literature. Overall, this review highlights promising potential of lipid-based treatment strategies further enhanced by the new knowledge of intraretinal lipids and lipoproteins in DR.