Tissue macrophages of fetal and adult origin have pivotal roles in tissue homeostasis and organ inflammation. Recently several functional and transcriptomic studies have revealed their unique module-like transcriptomic organization leading to enormous tissue-dependent functional plasticity. In this review, we discuss the development, tissue adaption and function of resident murine and human macrophages. Finally, we discuss our limited knowledge on human tissue macrophages and provide our opinion on their relevance during disease and for clinical application. At last we discuss a path towards a better understanding of human tissue macrophage populations using state of the art transcriptomic and epigenetic techniques to enable understanding of these powerful tissue-resident phagocytes.