At the site of inoculation, particulate fungal polysaccharides bind C-type lectin receptors (CLRs) and Fc receptors (FcRs), resulting in SYK activation via ITAM signaling in the receptor tail, the FcRγ signaling adaptor, or integrin receptor activation. The ensuing PKCδ and CARD9 activation is critical for caspase-1 and caspase-8 activity, MAP kinase signaling (not shown), NF-κB activation, and cytokine production. SYK-dependent PLCγ2 activation is linked to NADPH oxidase assembly and calcineurin-dependent NFAT activation. Dectin/SYK signaling controls IRF5-dependent IFN-γ production. VAV1 and BTK can interact with dectin-1 to mediate phagocytosis of Candida albicans in macrophages. BTK may also promote calcineurin activation and the production of NFAT-regulated cytokines. The model depicts fungal killing in the phagosome. Myeloid cell–derived cytokines promote the differentiation of both Th1 cells and Th17 cells. Th17 and innately derived IL-17 activate epithelial responses that coordinate clearance of fungal cells at mucosal surfaces. The asterisks indicate genetic or humoral defects that predispose humans to a spectrum of fungal disease. Myeloid and epithelial cells collaborate to regulate CXCR2-dependent neutrophil recruitment to portals of infection. Illustrated by Mao Miyamoto.