Plasticity and heterogeneity are hallmarks of myelomonocytic differentiation and polarized activation. Evidence published in this issue of the European Journal of Immunology, together with other recent data, add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation and are discussed in this Commentary. Heterogeneity and plasticity are hallmarks of cells belonging to the monocyte-macrophage lineage [1][2][3][4]. Lineage-defined populations of mononuclear phagocytes have not been identified, but already by the shortlived stage of circulating precursor monocytes subsets characterized by the differential expression of the FccRIII receptor (CD16) or of chemokine receptors (CCR2, CX3CR1 and CCR8) and by different functional properties have been described. Once in tissues, macrophages acquire distinct morphological and functional properties as directed both by the tissue (e.g. the gut macrophage) and the immunological microenvironment. Two papers published in this issue of the European Journal of Immunology [5,6], as well as other recently published reports [7][8][9][10][11], add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation.Multinucleated giant cells (MGC) are a prominent, characteristic feature of granulomas, which are caused by different agents but are exemplified by mycobacterial infections. MGC derive from the fusion of macrophages and, although different molecules have been implicated in the formation of MGC including TREM2, CD44 and more recently the P 2 X 7 nucleotide receptor [12], the molecular basis of their formation and their actual significance in chronic inflammation remains elusive. In the study by Helming and Gordon [6] in this issue of the Journal, the authors take advantage of a tagging strategy to determine that MGC formation is a multistep process associated with IL-4-driven alternative (M2) macrophage activation. The approach described in this study [6] is likely to pave the way to the identification of the pathways involved in and the function of MGC formation.In response to cytokines and microbial products, mononuclear phagocytes express specialized and polarized functional properties [1][2][3][4]. Mirroring the Th1/Th2 nomenclature, many refer to polarized macrophages as M1 and M2 cells. Classically activated M1 macrophages have long been known to be induced by IFN-c either alone or in concert with microbial stimuli (e.g. LPS) or cytokines (e.g. TNF-a and GM-CSF). IL-4 and IL-13 have been found to be more than simple inhibitors of [7,8,10,11]. Intriguingly, the chemokine receptor CCR4 also plays a role in macrophage polarization, as indicated by the drift to M2 polarization observed in CCR4 -/-macrophages [13]. In general, M1 cells have an IL-12 high , IL-23 high , IL-10 low phenotype. They are efficient producers of effector molecules (reactive oxygen and nitrogen intermediates) and inflammatory cytokines (IL-1b, TNF-a, IL-6), and participate as inducers and effect...