Macrophages are ubiquitously present innate immune cells in humans and animals belonging to both invertebrates and vertebrates. These cells were first recognized by Elia Metchnikoff in 1882 in the larvae of starfish upon insertion of thorns of tangerine tree and later in Daphnia magna or common water flea infected with fungal spores as cells responsible for the process of phagocytosis of foreign particles. Elia Metchnikoff received the Noble prize (Physiology and Medicine) for his discovery and describing the process of phagocytosis in 1908. More than 130 years have passed and different subtypes and roles of macrophages as innate immune cells have been established by the researchers. In addition to their immunoregulatory role in immune homeostasis and pathogenic infection, they also play a crucial role in the pathogenesis of sterile inflammatory conditions including autoimmunity, obesity, and cancer. The present chapter describes the immunoregulatory role of macrophages in the homeostasis and inflammatory diseases varying from autoimmunity to metabolic diseases including obesity.