The immune system balances protective immunity against pathogens with tolerance to self and selected foreign antigens. Emerging evidence identifies erythropoietin (EPO) as a systemic immunoregulatory signal that links physiological stress to immune adaptation. Beyond its canonical role in erythropoiesis, EPO–EPO receptor (EPOR) signaling reprograms specialized myeloid cells, including macrophages and type 1 conventional dendritic cells (cDC1s), promoting efferocytosis, inflammatory restraint, and maturation-associated cDC1 fate. Through these mechanisms, EPO shapes antigen-specific T-cell responses across transplantation and cancer. We propose that the EPO–EPOR axis functions as a systemic regulator of immune adaptation through myeloid-cell programming.