The NLR family of innate immune and cell death sensors plays a critical role in detecting pathogenic and sterile triggers, initiating inflammatory and anti-inflammatory signaling, and driving cell death pathways such as pyroptosis and PANoptosis. NLRs are cytosolic pattern recognition receptors that sense a wide range of microbial components and host-derived damage signals, leading to the formation of inflammasomes and the activation of caspase-1, which processes inflammatory cytokines like IL-1β and IL-18. Some NLRs are integral components of larger cell death complexes, such as PANoptosomes, which drive lytic cell death. The NLR family includes several subfamilies, such as NLRA (CIITA), NLRB (NAIP), NLRC (NOD1, NOD2, NLRC3, NLRC4, NLRC5), NLRP (NLRP1, NLRP3, NLRP6, NLRP9, NLRP12), and NLRX (NLRX1), each with distinct functions in immune signaling, cell death, and disease. NLRs are involved in a variety of physiological processes, including immune responses, inflammation, and homeostasis. Mutations in NLRs can lead to aberrant inflammation and disease, making them potential therapeutic targets. NLRs also form networks that connect innate immune sensing with cell death, and their dysfunction is associated with a range of diseases, including inflammatory disorders, cancer, and metabolic conditions. Understanding the mechanisms of NLR function and their interactions is crucial for developing therapies for infectious and inflammatory diseases, as well as cancer.The NLR family of innate immune and cell death sensors plays a critical role in detecting pathogenic and sterile triggers, initiating inflammatory and anti-inflammatory signaling, and driving cell death pathways such as pyroptosis and PANoptosis. NLRs are cytosolic pattern recognition receptors that sense a wide range of microbial components and host-derived damage signals, leading to the formation of inflammasomes and the activation of caspase-1, which processes inflammatory cytokines like IL-1β and IL-18. Some NLRs are integral components of larger cell death complexes, such as PANoptosomes, which drive lytic cell death. The NLR family includes several subfamilies, such as NLRA (CIITA), NLRB (NAIP), NLRC (NOD1, NOD2, NLRC3, NLRC4, NLRC5), NLRP (NLRP1, NLRP3, NLRP6, NLRP9, NLRP12), and NLRX (NLRX1), each with distinct functions in immune signaling, cell death, and disease. NLRs are involved in a variety of physiological processes, including immune responses, inflammation, and homeostasis. Mutations in NLRs can lead to aberrant inflammation and disease, making them potential therapeutic targets. NLRs also form networks that connect innate immune sensing with cell death, and their dysfunction is associated with a range of diseases, including inflammatory disorders, cancer, and metabolic conditions. Understanding the mechanisms of NLR function and their interactions is crucial for developing therapies for infectious and inflammatory diseases, as well as cancer.