Dectin-1 is a major β-glucan receptor on macrophages. Zymosan, a β-glucan- and mannan-rich particle, is widely used to study phagocyte responses. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) were historically considered major macrophage lectins involved in nonopsonic recognition of zymosan. However, using specific carbohydrate inhibitors, the study shows that a β-glucan receptor, not the MR, is predominant in this process. CR3 was not the β-glucan receptor mediating this activity. The recently described β-glucan receptor, Dectin-1, was shown to be almost exclusively responsible for β-glucan-dependent, nonopsonic recognition of zymosan by primary macrophages. These findings define Dectin-1 as the leukocyte β-glucan receptor, resolving the long-standing controversy about its identity. Dectin-1 is also identified as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design. The study used specific reagents to define the receptors involved in nonopsonic recognition of zymosan and soluble β-glucans in primary macrophages. It was shown that neither the MR nor CR3 were significantly involved, rather Dectin-1 played a major role. These results suggest that Dectin-1 is a major receptor for unopsonized zymosan on macrophages and that it can also contribute to the recognition of opsonized zymosan particles. The study also shows that Dectin-1 is expressed on the surface of macrophages and is not restricted to cells of the dendritic cell lineage. The identification of Dectin-1 as a major leukocyte β-glucan receptor defines the fundamental mechanism of β-glucan recognition by macrophages that has remained elusive since its first description over five decades ago. Dectin-1 could play a central role in the innate recognition of these carbohydrate polymers and may be a therapeutic target for novel drug design.Dectin-1 is a major β-glucan receptor on macrophages. Zymosan, a β-glucan- and mannan-rich particle, is widely used to study phagocyte responses. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) were historically considered major macrophage lectins involved in nonopsonic recognition of zymosan. However, using specific carbohydrate inhibitors, the study shows that a β-glucan receptor, not the MR, is predominant in this process. CR3 was not the β-glucan receptor mediating this activity. The recently described β-glucan receptor, Dectin-1, was shown to be almost exclusively responsible for β-glucan-dependent, nonopsonic recognition of zymosan by primary macrophages. These findings define Dectin-1 as the leukocyte β-glucan receptor, resolving the long-standing controversy about its identity. Dectin-1 is also identified as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design. The study used specific reagents to define the receptors involved in nonopsonic recognition of zymosan and soluble β-glucans in primary macrophages. It was shown that neither the MR nor CR3 were significantly involved, rather Dectin-1 played a major role. These results suggest that Dectin-1 is a major receptor for unopsonized zymosan on macrophages and that it can also contribute to the recognition of opsonized zymosan particles. The study also shows that Dectin-1 is expressed on the surface of macrophages and is not restricted to cells of the dendritic cell lineage. The identification of Dectin-1 as a major leukocyte β-glucan receptor defines the fundamental mechanism of β-glucan recognition by macrophages that has remained elusive since its first description over five decades ago. Dectin-1 could play a central role in the innate recognition of these carbohydrate polymers and may be a therapeutic target for novel drug design.