Release of angiogenic factors in response to the ischaemic retina is currently the most favoured hypothesis for the pathogenesis of proliferative diabetic retinopathy. Reducing the stimulus for angiogenesis by destroying the ischaemic retina also forms the basis of the most effective treatment of diabetic retinopathy by photocoagulation. Though ischaemia is undoubtedly important for neovascularization, there is recent evidence which cast doubts on ischemia being the sole mechanism for diabetic retinopathy. Many clinical observations viz. the protective effects of glaucoma, myopia, unilateral carotid stenosis on diabetic retinopathy; and its worsening after cataract extraction are not adequately explained by the present hypothesis. Moreover, the recent in vitro culture studies on retinal pigment epithelial cells have suggested an alternative explanation for the effectiveness of photocoagulation in proliferative diabetic retinopathy. Furthermore, hyperglycemia has been strongly correlated with the incidence and progression of diabetic retinopathy, but has only been indirectly indicted in its pathogenesis. These facts can be integrated into a more plausible hypothesis for the pathogenesis of diabetic retinopathy. It is hypothesized that a relative reduction in intra-ocular pressure caused by persistent or intermittent hyperglycemia may be the missing link that induces certain morphological changes in the retinal pigment epithelium. These changes, in addition to the ischaemic retina, may be important for the pathogenesis of diabetic retinopathy. Such a hypothesis also explains most of the hitherto unexplained features of diabetic retinopathy.