Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrated that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages resulted in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduced peritoneal macrophage populations and increased the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM were replaced by monocyte-derived LpM decreased the number of lesions that developed. We propose a putative model whereby endometrial macrophages are “pro-endometriosis” while newly recruited monocyte-derived macrophages, possibly in LpM form, are “anti-endometriosis.” These observations highlight the importance of monocyte-derived macrophages in limiting disease progression. During the seminar I will also touch on some of our scRNA-Seq data interrogating peritoneal and lesion-resident macrophages in the mouse model.