Extracellular nucleotides: pleiotropic players in the maintenance of homeostasis. A prospective overview of the role played by eNTPs in modulating responses to danger and how purinergic pathway integrates with immunomodulatory responses. Several insults can contribute to subvert the homeostatic condition in the hematopoietic system. Infective agents, ionizing radiations, chemical insults, and mechanical stress contribute to the release of nucleotides into the extracellular environment and the engagement of P2Rs on target cells (HSCs, regulatory T cells, MSCs, and endothelial progenitor cells), where eNTPs can cooperate in containing damage at different levels: (1) stimulate HSC proliferation and the subsequent production of immune effectors that will invigorate defense mechanisms; (2) attract HSCs, in synergy with other chemokines (eg, CXCL12), toward sites of inflammation and infection to activate tissue repair; and (3) contain detrimental effects of prolonged inflammation and immune responses acting on mature immune cells (eg, regulatory T cells). The net result of such a widespread effect on the hematopoietic system is aimed at damage containment and return to homeostatic conditions. EPC indicates endothelial progenitor cells.