(A) Trained immunity as induced by β-glucan mediates a myelopoiesis bias in the bone marrow. CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitor; HSC, hematopoietic stem cell; MPP, multi-potent progenitor. (B) The β-glucan-dependent myelopoiesis bias is mediated by an early-activated IL-1β pathway associated with enhanced glycolysis and lipid metabolism changes in hematopoietic stem and progenitor cells (HSPC) resulting in enhanced cholesterol-rich membrane microdomains and thereby enhanced GM-CSF/CD131 signaling, which drives myelopoiesis. (C) Induction of trained immunity in HSPCs protects them from LPS-induced DNA damage and enables beneficial responses of the bone marrow to a secondary LPS challenge as well as to chemotherapy-induced myelosuppression.