Neurodegeneration is an important component of diabetic retinopathy as demonstrated by increased neural apoptosis in the retina during experimental and human diabetes. Accumulation of sorbitol and fructose and the generation or enhancement of oxidative stress has been reported in the whole retina of diabetic animals. Aldose reductase (AR), the first and the rate limiting enzyme in the pathway reduces glucose to sorbitol and the diabetic complications are prevented by drugs that inhibit AR. In this study we examined the phosphorylation state of various retinal proteins in response to sorbitol-treatment by phospho-site-specific antibody microarray. Our results suggest that various retinal protein kinases and cytoskeletal proteins either activated or down regulated in response to sorbitol treatment. Further, our study also indicates the activation of retinal insulin- and insulin growth factor 1 receptor and their downstream signaling proteins such as phosphoinositide 3-kinanse and protein kinase B (Akt). Understanding the regulation of retinal proteins involved in polyol (sorbitol) pathway would help to design therapeutic agents for the treatment of diabetic retinopathy.