Macrophages, Monocyte, and Dendritic Cells (DCs) are myeloid cells, phagocytes, and effectors cells of the innate immune system. Despite the identification of a number of phenotypic subsets, our understanding of the functions of these cells in vivo remains largely incomplete. Recent fate-mapping studies from our lab have identified a dual developmental origin for macrophages, monocytes and DCs. Monocytes, some tissue monocyte/macrophage subsets, such as in the adult gut, classical DCs and plasmacytoid DCs, develop and renew in vivo from c-Myb-dependent Hematopoietic Stem and Progenitors Cells (HSPCs) and require require the transcription factor for its development and express Csf1R and Flt3. In contrast a large number of ‘resident’ tissue macrophage networks, including liver Kuppfer cells, epidermal Langerhans cells, brain microglia, alveolar macrophages, and a proportion of splenic red pulp and kidney macrophages, develop during embryogenesis and early post-natal life from Csf1R+ Yolk-Sac erythro-myeloid progenitors, that do not express Flt3- and develop in the absence of c-Myb-. The  Yolk-Sac erythro-myeloid progenitors colonize the fetal liver after E9, expand and give rise to the transient fetal liver hematopoiesis, and to definitive resident macrophage networks. These c-Myb-independent macrophages persist in adult mice, independently of HSPCs and c-Myb. We propose that differentiation of macrophages should be studied in the context of the development of macrophage networks.​