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The commencement of cancer is attributed to one or a few cells that become rogue and attain the property of immortality. The inception of distinct cancer cell clones during the hyperplastic and dysplastic stages of cancer progression is the utimate consequence of the dysregulated cellular pathways and the proliferative potential itself. Furthermore, a critical factor that adds a layer of complexity to this pre-existent intra-tumoral heterogeneity (ITH) is the foundation of an oxygen gradient, that is established due to the improper architecture of the tumor vasculature. Therefore, as a resultant effect, the poorly oxygenated regions thus formed and characterized as hypoxic, promote the emergence of aggressive and treatment-resistant cancer cell clones. The extraordinary property of the hypoxic cancer cells to exist harmoniously with cancerous and non-cancerous cells in the tumor microenvironment (TME) further increases the intricacies of ITH. Here in this review, the pivotal influence of differential oxygen concentrations in shaping the ITH is thoroughly discussed. We also emphasize on the vitality of the interacting networks that govern the overall fate of oxygen gradient-dependent origin of tumor heterogeneity. Additionally, the implications of less-appreciated reverse Warburg effect, a symbiotic metabolic coupling, and the associated epigenetic regulation of rewiring of cancer metabolism in response to oxygen gradients, have been highlighted as critical influencers of ITH., (Copyright © 2021 Elsevier B.V. All rights reserved.)