Macrophages in tissues arise from at least 3 distinct sources. During primitive hematopoiesis macrophages arise from the YS independent of HSC precursors and populate the brain, constituting the major brain macrophage lineage, microglia. Additionally, the fetal liver is populated with YS-derived macrophages and become the major source of tissue resident macrophages (TRM) in the lung, spleen, liver, pancreas and kidney. Bone-marrow derived macrophages (BDM) constitute yet a third source of macrophages, which can populate all major organs upon homeostatic adaptations, infection, disease or cancer.