The Hypoxia-adenosinergic regulation of immune response and tissue damage will be described. This mechanism is important in limiting the collateral damage to normal and still healthy tissues during acute inflammation caused by pathogens or treauma. This mechanism protects normal tissues by down-regulating the effector functions of overactive immune cells. Misquidedly, the same mechanism also protects cancerous tissues from anti-tumor effects of tumor-recognizing anti-tumor T cells, The Gs protein coupled A2A and A2B adenosine receptors play critical role in the Hypoxia-adenosinergic regulation with Hypoxia Inducible Factor -1alpha being additive or –possibly- synergistic with immunosuppressive effects of extracellular adenosine on CD4+ and CD8+ T cells. The medical implications of targeting the hypoxia-adenosinergic mechanism range from sepsis to cancer to acute and chronic liver and lung inflammation to the use of supplemental oxygen with ARDS, COPD and postoperative patients in intensive care units.