The evolutionarily selected tissue-protecting mechanisms are likely to be triggered by an event of universal significance for all surrounding cells. Such an event could be damage to blood vessels, which would result in local tissue hypoxia. It is now recognized that tissue hypoxia can initiate the tissue-protecting mechanism mediated by at least two different biochemical pathways. The central message of this review is that tumor cells are protected from immune damage in hypoxic and immunosuppressive tumor microenvironments due to the inactivation of anti-tumor T cells by the combined action of these two hypoxia-driven mechanisms. Firstly, tumor hypoxia-produced extracellular adenosine inhibits anti-tumor T cells via their G_s-protein-coupled and cAMP-elevating A2A and A2B adenosine receptors (A2AR/A2BR). Levels of extracellular adenosine are increased in tumor microenvironments due to the changes in activities of enzymes involved in adenosine metabolism. Secondly, TCR-activated and/or tumor hypoxia-exposed anti-tumor T cells may be inhibited in tumor microenvironments by Hypoxia-inducible Factor 1α (HIF-1α) Hence, HIF-1α activity in T cells may contribute to the tumor-protecting immunosuppressive effects of tumor hypoxia. Here, we summarize the data that support the view that protection of hypoxic cancerous tissues from anti-tumor T cells is mediated by the same mechanism that protects normal tissues from the excessive collateral damage by overactive immune cells during acute inflammation.