Ayurveda, an ancient Indian system of medicine documented and practised since 1500 B.C., follows a systems approach that has interesting parallels with contemporary personalized genomic medicine approaches to the understanding and management of health and disease. It is based on the trisutra, which are the three aspects of causes, features and therapeutics that are interconnected through a common organizing principle termed ‘tridosha’. Tridosha comprise three ascertainable physiological entities; vata (kinetic), pitta (metabolic) and kapha (potential) that are pervasive across systems, work in conjunction with each other, respond to the external environment and maintain homeostasis. Each individual is born with a specific proportion of tridosha that are not only genetically determined but also influenced by the environment during foetal development. Jointly they determine a person’s basic constitution, which is termed their ‘prakriti’. Development and progression of different diseases with their subtypes are thought to depend on the origin and mechanism of perturbation of the doshas, and the aim of therapeutic practice is to ensure that the doshas retain their homeostatic state. Similarly, western systems biology epitomized by translational P4 medicine envisages the integration of multiscalar genetic, cellular, physiological and environmental networks to predict phenotypic outcomes of perturbations. In this perspective article, we aim to outline the shape of a unifying scaffold that may allow the two intellectual traditions to enhance one another. Specifically, we illustrate how a unique integrative ‘Ayurgenomics’ approach can be used to integrate the trisutra concept of Ayurveda with genomics. We observe biochemical and molecular correlates of prakriti and show how these differ significantly in processes that are linked to intermediate patho-phenotypes, known to take different course in diseases. We also observe a significant enrichment of the highly connected hub genes which could explain differences in prakriti, focussing on EGLN1, a key oxygen sensor that differs between prakriti types and is linked to high altitude adaptation. Integrating our observation with the current literature, we demonstrate how EGLN1 could qualify as a molecular equivalent of tridosha that can modulate different phenotypic outcomes, where hypoxia is a cause or a consequence both during health and diseased states. Our studies affirm that integration of the trisutra framework through Ayurgenomics can guide the identification of predisposed groups of individuals and enable discovery of actionable therapeutic points in an individualized manner. © 2016, Indian Academy of Sciences.