Skin-based DCs and macrophages sense invading pathogens and serve as sentinels, thereby alerting effectors of the innate and adaptive immune systems to potential danger to the host. Subsets of immune sentinels include CD1a⁺Langerin⁺ LCs located in the epidermis and various subtypes of DCs and macrophages in the dermis. In this issue of the JCI, Zaba et al. (17) used mixed leukocyte assay to identify BDCA-1⁺ DDCs as the major immunostimulatory population in normal human skin. In addition, they found that the mononuclear cells expressing CD163 were less immunostimulatory, but possessed greater phagocytic activity and morphological features of macrophages. These recent morphological, immunophenotypic, and functional findings complement previous studies that defined additional mononuclear subsets including: PDCs, which are relatively rare in normal skin but are capable of producing type I IFNs and express BDCA-2, IL-3 receptor α (IL-3Rα), and CD45RA; CD14⁺ DDCs, which may develop into LCs under the influence of TGF-β; TNF- and iNOS-producing DCs (TIP-DC), characterized by their production of TNF-α and iNOS; and various macrophage subsets. Currently the macrophage population expressing CD68 and CD14 can be further subdivided into classically activated macrophages (M1), developing under the influence of LPS and IFN-γ, and alternatively activated macrophages (M2), developing under the influence of IL-4 and IL-10. The M1 type macrophage expresses CD16, CD32, and CD64, whereas the M2 type macrophage expresses CD163, FXIIIa, MR, and the marker RM3/1 as previously described (15). Circular arrows indicate the self-renewing potential of LCs and DDCs under conditions of tissue homeostasis. Moreover, circulating blood-derived monocytes are potential precursors of LCs, DDCs, and macrophages, especially under inflammatory conditions.