Abstract: The eye is the only place in the human body where blood flow and systemic vascular features can be observed and measured easily and non-invasively down to the capillary level. Numerous clinical studies have shown correlations between alterations in ocular blood flow and ocular diseases (e.g. glaucoma, age-related macular degeneration, diabetic retinopathy), neurodegenerative diseases (e.g. Alzheimer’s disease, Parkinson’s disease) and other systemic diseases (e.g. hypertension, diabetes). Thus, deciphering the mechanisms governing ocular blood flow could be the key to the use of eye examinations as a non-invasive approach to the diagnosis and continuous monitoring for many patients. However, many factors influence ocular hemodynamics, including intraocular pressure (IOP), blood pressure and blood flow autoregulation, and it is extremely challenging to single out their individual contributions during clinical and animal studies. In the recent years, we have been developing mathematical models and computational methods to aid the interpretation of clinical data. In this talk, we will present models describing (i) the blood flow in the ocular macro- and micro-vasculature, accounting for the IOP-induced deformation of the vessel walls; (ii) the regulation of blood flow in the retina, accounting for the myogenic, shear-stress, carbon dioxide (CO2) and oxygen (O2) responses, as well as the role of nitric oxide (NO) in mediating neural signals to the vessel walls; (iii) O2 transport, diffusion and consumption in the retinal vasculature and tissue. Results will show how the synergy between mathematical modeling and clinical data allowed us to estimate the relative contribution of IOP, blood pressure and blood flow autoregulation on ocular tissue perfusion and vessel mechanics, and to distinguish disease mechanisms in different subgroups of glaucoma patients. Current efforts in translating this multiscale/multiphysics modeling methods into clinical resources to be used for individualized approaches to disease diagnosis and treatment will also be discussed.