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Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs)^,,, however, macrophages in adult tissues can self-maintain independently of HSCs^,,,. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs^,,,,,, and fetal macrophages^,, can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues^,,. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2⁺ (also known as Tek) cellular pathway generating Csf1r⁺ erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk …