Dectin-1 mediates the biological effects of β-glucans. Fungal-derived β-glucan particles induce leukocyte activation and the production of inflammatory mediators, such as TNF-α. The receptors involved in these responses are unknown. This study shows that Dectin-1 mediates TNF-α production in response to zymosan and live fungal pathogens. This activity occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens. β-glucans possess anti-infective and anti-tumorigenic properties that stem from their ability to activate leukocytes. These fungal-derived carbohydrates are widely used to examine the proinflammatory responses of phagocytes. Despite almost 50 years of examination, the receptor(s) mediating these effects are still undefined. Dectin-1 was identified as a β-glucan receptor by screening a RAW264.7 cDNA library with zymosan. Dectin-1 is a small type II transmembrane receptor containing one lectin-like carbohydrate recognition domain, which recognizes β1,3- and/or β1,6-linked glucans and intact yeast. It also contains an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail. In addition to these exogenous ligands, the receptor can also recognize an endogenous ligand on T cells. The receptor is expressed at high levels on macrophages and neutrophils, and to a lesser extent on dendritic cells and a subpopulation of T cells. The study shows that Dectin-1 acts as a major receptor for zymosan and other β-glucans on macrophages. It mediates cellular responses to zymosan as well as to live yeast pathogens. The response occurs at the cell surface and requires the cytoplasmic tail of this receptor and the Toll-like receptor (TLR) pathway. These results are the first evidence that the proinflammatory response requires recognition by pathogen-specific receptors in addition to the TLRs, and does not require pathogen internalization. The study also shows that Dectin-1 is involved in the production of TNF-α in response to live yeast pathogens. The TLR pathway is also required to trigger the proinflammatory response to zymosan. TLRs are thought to sample the phagosomal contents, triggering a response appropriate to the pathogen. BMDM from TDectin-1 mediates the biological effects of β-glucans. Fungal-derived β-glucan particles induce leukocyte activation and the production of inflammatory mediators, such as TNF-α. The receptors involved in these responses are unknown. This study shows that Dectin-1 mediates TNF-α production in response to zymosan and live fungal pathogens. This activity occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens. β-glucans possess anti-infective and anti-tumorigenic properties that stem from their ability to activate leukocytes. These fungal-derived carbohydrates are widely used to examine the proinflammatory responses of phagocytes. Despite almost 50 years of examination, the receptor(s) mediating these effects are still undefined. Dectin-1 was identified as a β-glucan receptor by screening a RAW264.7 cDNA library with zymosan. Dectin-1 is a small type II transmembrane receptor containing one lectin-like carbohydrate recognition domain, which recognizes β1,3- and/or β1,6-linked glucans and intact yeast. It also contains an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail. In addition to these exogenous ligands, the receptor can also recognize an endogenous ligand on T cells. The receptor is expressed at high levels on macrophages and neutrophils, and to a lesser extent on dendritic cells and a subpopulation of T cells. The study shows that Dectin-1 acts as a major receptor for zymosan and other β-glucans on macrophages. It mediates cellular responses to zymosan as well as to live yeast pathogens. The response occurs at the cell surface and requires the cytoplasmic tail of this receptor and the Toll-like receptor (TLR) pathway. These results are the first evidence that the proinflammatory response requires recognition by pathogen-specific receptors in addition to the TLRs, and does not require pathogen internalization. The study also shows that Dectin-1 is involved in the production of TNF-α in response to live yeast pathogens. The TLR pathway is also required to trigger the proinflammatory response to zymosan. TLRs are thought to sample the phagosomal contents, triggering a response appropriate to the pathogen. BMDM from T