As far back as 1882, Ilya (Elie) Metchnikoff was the first to discover macrophages (MΦ) and their important role in host defense [1]. Now, almost 140 years later, MΦ are known as incredible cell types with unique functions and capabilities. In fact, Ilya Metchnikoff paved our understanding of peripheral blood monocytes and MΦ in the clearance of pathogens, while follow-up studies described MΦ in various organs in which their defined functions are directly linked to a divergent onset (Fig. 1). MΦ are found in all organs, typically forming a threedimensional network that supports tissue function by production of growth factors and phagocytosis of dead and dying cells during steady state. Moreover, MΦ are among the first cells encountering pathogens, debris, or tumor cells in diseased tissue. Given these and other multifarious functions and their important role in the onset and/or progression of various diseases, MΦ are therefore rendered as a perfect candidate in cell-based immunotherapies. Against a great body of newly emerging data, scientists still encounter in the MΦ research literature the terminology of MΦ polarization, most commonly into the M1 (classically activated) and M2 (alternatively activated) phenotypes (see also review [2]). Thus, also therapy approaches aim at using this apparent plasticity of MΦ and “simply” try to switch them from M1 to M2 or the other way around, depending on whether anti-or pro-inflammatory responses are required. However, these M1/M2 definitions stem from cells treated with interferon-γ or interleukin-4, respectively, and ignore the fact that these defined and isolated stimuli in vitro do not emerge in vivo. In contrast, under physiological conditions a plethora of stimuli (eg, cytokines, bacteria, foreign antigens, or the tissue niche) modulate MΦ function in an orchestrated fashion, which can be difficult to recapitulate in vitro [2].