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Macrophages are important cells in the host resistance to fungal infections, and fungal recognition by macrophages triggers phagocytosis, intracellular killing, induction of inflammatory cytokines and chemokines, and initiation of the adaptive immune response. All of the receptors that mediate binding and engulfment of fungal pathogens and the signaling pathways triggered by fungal pathogens that regulate anti-fungal immunity are not fully understood. Using an RNAi screen we recently demonstrated that the C. elegans receptors CED-1 and C03F11.3, and their mammalian orthologues, the scavenger receptors SCARF1 and CD36 mediate host defense against the fungal pathogen, Cryptococcus neoformans. Finally, SCARF1 and CD36 function as co-receptors by binding and engulfing fungal pathogens to facilitate Toll-like receptor 2 signaling. Here we will summarize and expand upon our previous findings.