This study identifies and characterizes Nod2, a novel member of the Nod1/Apaf-1 family of proteins. Nod2 is composed of two N-terminal CARDs, a nucleotide-binding domain (NBD), and multiple C-terminal leucine-rich repeats (LRRs). Unlike Nod1 and Apaf-1, which are widely expressed in tissues, Nod2 is highly restricted to monocytes. Nod2 induces NF-κB activation through interactions with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. The ability of Nod2 to activate NF-κB correlated with its interaction with RICK and was inhibited by dominant negative mutants of RICK. The study also demonstrates that enforced oligomerization of Nod2, mediated by its CARDs, is sufficient for NF-κB activation. These findings suggest that Nod2 functions as a receptor for bacterial components in monocytes, transducing signals that lead to NF-κB activation and transcription of regulatory genes.This study identifies and characterizes Nod2, a novel member of the Nod1/Apaf-1 family of proteins. Nod2 is composed of two N-terminal CARDs, a nucleotide-binding domain (NBD), and multiple C-terminal leucine-rich repeats (LRRs). Unlike Nod1 and Apaf-1, which are widely expressed in tissues, Nod2 is highly restricted to monocytes. Nod2 induces NF-κB activation through interactions with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. The ability of Nod2 to activate NF-κB correlated with its interaction with RICK and was inhibited by dominant negative mutants of RICK. The study also demonstrates that enforced oligomerization of Nod2, mediated by its CARDs, is sufficient for NF-κB activation. These findings suggest that Nod2 functions as a receptor for bacterial components in monocytes, transducing signals that lead to NF-κB activation and transcription of regulatory genes.