A scientific literature that covers 150 years of research indicates that a cell type found in most tissues, conserved across metazoans, and commonly designed as ‘macrophages’ in vertebrates participates to the niches that support specialized tissues cells, acting as sentinel for the uptake of dying cells and pathogens, regulator of morphogenesis and tissue remodeling, homeostasis and metabolism, and are involved in inflammatory processes, degenerative diseases and tumor growth. The overarching hypothesis that drives our work is that understanding of the development, specification, growth, and organization of macrophages within tissues is essential to the molecular characterization of their functions at the tissue and organismal level and for the identification of genetic events, including germ-line polymorphisms and somatic mosaicism that cause macrophage dysfunction and disease pathogenesis