Macrophages are strategically located throughout the body, where they play crucial roles in immune defense, tissue homeostasis, and disease. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. This review discusses the four stages of orderly inflammation mediated by macrophages: recruitment to tissues, differentiation and activation in situ, conversion to suppressive cells, and restoration of tissue homeostasis. The protective and pathogenic functions of various macrophage subsets are also discussed, including their roles in antimicrobial defense, antitumor immune responses, metabolism, obesity, allergy, asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis, and wound healing. The review highlights the challenges in characterizing macrophage heterogeneity in humans and emphasizes the need for further research to understand the complex mechanisms regulating macrophage activation and deactivation in both health and disease.Macrophages are strategically located throughout the body, where they play crucial roles in immune defense, tissue homeostasis, and disease. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. This review discusses the four stages of orderly inflammation mediated by macrophages: recruitment to tissues, differentiation and activation in situ, conversion to suppressive cells, and restoration of tissue homeostasis. The protective and pathogenic functions of various macrophage subsets are also discussed, including their roles in antimicrobial defense, antitumor immune responses, metabolism, obesity, allergy, asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis, and wound healing. The review highlights the challenges in characterizing macrophage heterogeneity in humans and emphasizes the need for further research to understand the complex mechanisms regulating macrophage activation and deactivation in both health and disease.