Immunoreceptor tyrosine-based activation motifs (ITAMs) play crucial roles in antigen-receptor signaling in acquired immunity. Although receptors associated with the ITAM-bearing adaptors FcRγ and DAP12 on myeloid cells have been suggested to activate innate immune responses, the mechanism coupling those receptors to ‘downstream’ signaling events is unclear. The CARMA1–Bcl10–MALT1 complex is critical for NF-κB activation in lymphocytes but has an unclear role in myeloid cells. Here, we report that genetic deletion of the gene encoding the Bcl10-binding partner CARD9 resulted in impaired myeloid cell activation of NF-κB signaling by several ITAM-associated receptors. We also demonstrated that CARD9 is required for Toll-like receptor (TLR)-induced dendritic cell (DC) activation via MAP kinase activation. Whereas Bcl10–/– and Card9–/– mice exhibited similar signaling impairments for myeloid cells, Card11–/– myeloid cell responses were normal; and whereas Card11–/– lymphocytes are defective in antigen receptor-mediated activation, Card9–/– lymphocytes were not. Thus, the activation of lymphoid and myeloid cells through ITAM-associated receptors or TLRs is regulated by CARMA1–Bcl10 and CARD9–Bcl10, respectively.