Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Bastos et al. uncover the requirements for monocytes to replace microglia and border-associated macrophages. They show that monocyte ontogeny shapes brain macrophage identity, with fetal monocytes acquiring a true microglial state. Using xenotransplantation and Alzheimer’s patient data, they identify human monocyte-derived microglia. These findings are important for microglia replacement therapies.