Diabetic retinopathy remains the most frequent cause of new cases of blindness among adults aged 20-74 years. A number of large trials have validated that laser photocoagulation is a useful treatment but the disease continues to progress in approximately 50% of eyes treated by photocoagulation. Other forms of therapy that are targeted at the earliest stages of retinal disease are needed. Recent research suggests that they may be available, but their efficacy cannot be tested due to the lack of accepted methods which detect and follow the initial changes occurring in the diabetic retina. Fundus photography, still widely considered the method of choice for following diabetic retinopathy, cannot identify the initial changes. All the other accepted clinical endpoints only give indications on the late stages of the retinopathy. Reduction in fluorescein leakage and reduction in retinal thickness are the most likely candidates for surrogate outcomes so that drugs may be tested in the initial stages of diabetic retinopathy. Instrumentation to measure retinal fluorescein leakage and retinal thickness is presented. The Retinal Leakage Analyzer is capable of measuring fluorescein leakage and mapping alterations of the Blood-Retinal Barrier. To measure retinal thickness, the Retinal Thickness Analyzer is shown to be more sensitive than Optical Coherence Tomography when following the initial stages of retinal disease. The results of the first one-year follow-up of eyes with minimal diabetic retinal disease show that retinal fluorescein leakage and retinal thickness measurements are extremely promising tools to evaluate new medical therapies for diabetic retinopathy.