Immune regulatory proteins such as CIITA, NAIP, IPAF, NOD1, NOD2, NALP1, and cryopyrin (also known as NALP3) are members of a family characterized by the presence of a NACHT nucleotide-binding domain (NBD) and leucine-rich repeats (LRRs). Members of this gene family encode a protein structure similar to the NB-LRR subgroup of disease-resistance genes in plants and are involved in the sensing of pathogenic products and the regulation of cell signaling and death. Currently, a variety of different names are used to describe the products encoded by the NBD and LRR containing gene family, its subfamilies, and individual genes, including CATERPILLER (CLR), NOD-LRR, NACHT-LRR, NOD-like receptor, CARD, NALP, NOD, PAN, and PYPAF. This lack of consistency has led to a pressing need to unify the nomenclature for this gene family. Consequently, we propose a standardized nomenclature, NLR, which stands for the nucleotide-binding domain and leucine-rich repeat containing gene family. The NLR family includes several subfamilies distinguishable by their N-terminal effector domains. There are four recognizable NLR N-terminal domains: acidic transactivation domain, pyrin domain, caspase recruitment domain (CARD), and baculoviral inhibitory repeat (BIR)-like domains (see Table 1 for the human NLR genes). These N-terminal domains have been used by several groups to subdivide the NLR gene family, and there are now multiple names for each subfamily: the largest pyrin-containing subfamily has been named PAN, NALP, and PYPAF; members of the CARD-containing subfamily have been named CARDs or NODs; the BIR-containing subfamily has been named NAIP or BIRC. In consultation with over 100 scientists, through a stepwise voting process organized by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC) and conducted via email and updated web pages, a new nomenclature system for human and mouse NLR genes has been agreed upon (see Table S1 available online for human and mouse NLR genes). It was agreed that the family name ‘‘nucleotide-binding domain and leucine-rich repeat containing’’should be used to highlight these two evolutionarily conserved domains and to reflect the similarity of the NLR family to the plant NB-LRR proteins. Furthermore, the consensus of opinion was that a subfamily-derived nomenclature system based on the N-terminal effector domains should be implemented. Consequently, four subfamily designations have been approved: NLRA, NLR family, acidic domain containing; NLRB, NLR family, BIR domain containing; NLRC, NLR family, CARD domain containing; NLRP, NLR family, pyrin domain containing; NLRX, NLR family with no strong homology to the N-terminal domain of any other NLR subfamily member (Table 1). Each member within a subfamily is given a number, eg, NLRP1. Four members of the NLR family, CIITA, NAIP, NOD1, and NOD2, have not been renamed. These four genes are associated with a large volume of literature, and it was agreed that renaming these would cause confusion in the literature. However, each of these genes has been given a subfamily alias to enable electronic data-retrieval systems to link these four genes to the NLR gene family. Clearly related genes, such as NLRP10 and Naip3-6, that do not encode NBD and/or LRR are included for completeness and historic reasons.