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NOD‐like receptors (NLRs) constitute a family of intracellular PRRs. The primary role of these cytoplasmic receptors is to recognize cytoplasmic PAMPs and/or the endogenous danger signal, thereby inducing immune responses. NLRs are characterized by a tripartite‐domain organization with a conserved nucleotide‐binding oligomerization domain (NOD) and leucine‐rich repeats (LRRs). Certain NLRs can assemble into a multiprotein complex called the inflammasome, which activates an enzyme called caspase‐1 that can cleave immature forms of certain cytokines, such as IL‐1 into active, mature cytokines (Figure 3.6). As the name implies, generation of inflammasomes is associated with inflammatory responses triggered by microbial pathogens. Inflammation will be discussed later in this chapter. In this capacity, inflammasomes meaningfully contribute to the healthy resolution of infections. However, activation of inflammasomes also contributes to cytokine‐driven inflammation central to the pathology of autoimmune and autoinflammatory diseases. Consequently, inflammasomes are now major drug targets for autoimmune and chronic inflammatory diseases. Moreover, recent studies have described the genetic association of mutations in NLR genes with several chronic inflammatory barrier diseases, such as Crohn’s disease and asthma, and with rare autoinflammatory syndromes including familial cold urticaria, Muckle–Wells syndrome, and Blau syndrome.