Abstract: Macrophages are immune cells of myeloid origin and are present in almost all tissues. They perform a wide variety of functions contributing to tissue development, homeostasis, pathogenesis, and repair (Wynn et al., 2013). Strikingly, macrophages residing at different tissues, and at different compartments of an individual tissue, demonstrate enormously diverse molecular characteristics (Gordon and Taylor, 2005). Querying this exceptional molecular heterogeneity challenged the long-standing theory that adult tissue macrophages derive solely from circulating monocytes. Indeed, lineage tracing and fate mapping studies using chimeric and cre-floxed animal models, followed by RNA-sequencing, convincingly demonstrated that tissue resident macrophages also consist of a pool that originates from yolk-sac progenitor cells (YPC) (Ginhoux and Guilliams, 2016; De Schepper et al., 2018). For example, initial macrophages arise from primitive progenitor cells in the yolk-sac at embryonic day (E) 8.5. These macrophages migrate into developing tissues to generate long-term resident tissue macrophages. At E10.5, erythromyeloid progenitor cells from the yolk-sac enter the fetal liver giving rise to hematopoietic stem cells (HSCs), which will eventually generate fetal liver monocytes. The fetal liver monocytes then migrate into developing peripheral tissues to establish another pool of long-term resident tissue macrophages. In addition, the erythromyeloid progenitor cells seed bone marrow, and the resulting bone marrow HSCs then maintain the uninterrupted supply of circulating monocyte-derived macrophages in adult tissues (Ginhoux and Guilliams, 2016; Goldmann et al., 2016). Overall, adult tissues encompass a mix of YPC-derived and circulating monocyte-derived macrophages and they are molecularly distinct. Some examples of YPC derived macrophages include microglia, alveolar macrophages, Langerhans cells, Kupffer cells, peritoneal macrophages, cardiac macrophages, and a subset of macrophages in the peripheral nervous system (PNS) (Wynn et al., 2013; Wang et al., 2020; Ydens et al., 2020).