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