Macrophages are evolutionarily ancient immune cells that are essential for development, homeostasis, and host-defence. Macrophages seed the developing tissues early in embryonic development and contribute to the development and function of the organs throughout life. During infection and injury hematopoietic stem cells produce monocytes that home to the affected location and are exposed to microenvironmental cues that shape their maturation into macrophages. The diversity of macrophage functions - from clearing dead and dying cells to initiating inflammatory responses to pathogens - results from their ability to interpret and adapt to host and foreign signals using a diverse range of receptors and adapting their metabolism and transcriptional programming to the challenge at hand. Herein we review how macrophage origins and microenvironmental cues alter their phenotype and function in homeostasis and host defence. A diagram illustrating macrophage roles derived from HSC and EMP origins in immune pathology, tissue repair and debris clearance. The diagram shows macrophages derived from two sources: HSC (hematopoietic stem cells) and EMP (erythro-myeloid progenitors). HSC leads to monocytes, which differentiate into macrophages. Surrounding the macrophage are labeled roles: immune pathology, host defense, tissue repair, scarring, debris clearance, chronic inflammation and autoimmunity.