Despite significant research on many fronts, the global diabetes pandemic and its attendant complications remains complex and poorly understood. Proteomic approaches have been used to deal with these complexities through methods to increase the fractional abundance of low-abundant proteins, and to compare protein samples directly using either chemical labeling methods or label-free methods to identify and comparatively analyze proteins directly in the mass spectrometer. It is more likely that a single protein does not initiate disease progression but rather multiple vitreous-resident serum proteins likely contribute to the pathogenic mechanisms. Substantial work remains to understand better the initiation and progression of nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema in the context of why some type-1 diabetics and why many type-2 diabetics do not progress toward loss of vision and blindness.