Alterations in ocular blood flow have been identified as important risk factors for the onset and progression of numerous diseases of the eye. In particular, several population-based and longitudinal-based studies have provided compelling evidence of hemodynamic biomarkers as independent risk factors for ocular disease throughout several different geographic regions. Despite this evidence, the relative contribution of blood flow to ocular physiology and pathology in synergy with other risk factors and comorbidities (e.g., age, gender, race, diabetes and hypertension) remains uncertain. There is currently no gold standard for assessing all relevant vascular beds in the eye, and the heterogeneous vascular biomarkers derived from multiple ocular imaging technologies are non-interchangeable and difficult to interpret as a whole. As a result of these disease complexities and imaging limitations, standard statistical methods often yield inconsistent results across studies and are unable to quantify or explain a patient's overall risk for ocular disease. Combining mathematical modeling with artificial intelligence holds great promise for advancing data analysis in ophthalmology and enabling individualized risk assessment from diverse, multi-input clinical and demographic biomarkers. Mechanism-driven mathematical modeling makes virtual laboratories available to investigate pathogenic mechanisms, advance diagnostic ability and improve disease management. Artificial intelligence provides a novel method for utilizing a vast amount of data from a wide range of patient types to diagnose and monitor ocular disease. This article reviews the state of the art and major unanswered questions related to ocular vascular anatomy and physiology, ocular imaging techniques, clinical findings in glaucoma and other eye diseases, and mechanistic modeling predictions, while laying a path for integrating clinical observations with mathematical models and artificial intelligence. Viable alternatives for integrated data analysis are proposed that aim to overcome the limitations of standard statistical approaches and enable individually tailored precision medicine in ophthalmology.