Tissue-resident macrophages (TRMs) originate from the yolk sac and fetal liver during development and persist in many tissues via self-renewal. During homeostasis (left panel), TRMs clear apoptotic cells, proteins, and phospholipids and either clear or respond to toxins, particulates, and pathogens within the local microenvironment. Many TRMs are capable of maintaining themselves by local proliferation without the contribution of monocyte-derived macrophages (MoMs). TRMs produce a variety of factors that stimulate the activation, proliferation, and differentiation of immune cells, epithelial cells, endothelial cells, fibroblasts, and stem cells that facilitate tissue homeostasis. In response to tissue injury (middle panel), bone marrow–derived monocytes are recruited to the injured tissue, where they differentiate into MoMs. During injury, TRMs and MoMs play distinct roles; usually MoMs exhibit a more robust inflammatory response. During the resolution of injury (right panel), TRMs may die or expand through self-renewal and repopulate the niche. MoMs either undergo apoptosis or persist, sometimes gaining the capacity for self-renewal. Over time, the phenotypes of TRMs and MoMs become increasingly similar. Arrows indicate interactions with other cell types.