Little is known about the functional differences between the human skin myeloid dendritic cell (DC) subsets, epidermal CD207⁺ Langerhans cells (LCs) and dermal CD14⁺ DCs. We showed that CD14⁺ DCs primed CD4⁺ T cells into cells that induce naive B cells to switch isotype and become plasma cells. In contrast, LCs preferentially induced the differentiation of CD4⁺ T cells secreting T helper 2 (Th2) cell cytokines and were efficient at priming and crosspriming naive CD8⁺ T cells. A third DC population, CD14⁻CD207⁻CD1a⁺ DC, which resides in the dermis, could activate CD8⁺ T cells better than CD14⁺ DCs but less efficiently than LCs. Thus, the human skin displays three DC subsets, two of which, i.e., CD14⁺ DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity, respectively.