We sought to briefly describe current models of endogenous erythropoietin (EPO) pleiotropic properties to make four points clear. First, endogenous EPO regulates erythroid cell apoptosis so that red blood cell production is balanced against the number of cells destroyed in order to maintain optimal tissue oxygen levels (i.e., consistent with provision of homeostatic functional signaling information). Second, preclinical and clinical studies alike provide additional evidence of other (i.e., extraerythropoietic) immune-related and growth/trophic properties. Third, EPO might also be increased as an antiinflammatory response to other proinflammatory cytokines, and not because it is an inflammatory protein, in which case, it would make the association between EPO and these other proteins an epiphenomenon. Fourth, on the other hand, EPO might also act as a tissue protector or it could reflect immaturity/vulnerability of the brain or of the systems responsible for protecting it. Each of these scenarios is plausible, and all are probably true in certain circumstances.