Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of cytosolic pattern recognition receptors that detect pathogenic and sterile triggers. Upon activation, specific NLRs initiate pro- or anti-inflammatory signaling cascades and form inflammasomes, which induce caspase-1 activation to drive inflammatory cytokine maturation and pyroptosis. Certain NLRs and inflammasomes also form PANoptosomes, driving another form of lytic cell death, PANoptosis. This review discusses the evolution, structure, and function of NLR subfamilies in health and disease, highlighting their roles in driving cell death and immunity. Understanding NLR networks may provide therapeutic strategies for infectious and inflammatory diseases and cancer. The NLR family is diverse, with at least 23 members in humans and 34 in mice, and they have evolved to recognize distinct microbial components and host-derived damage-associated molecular patterns (DAMPs). NLRs can function as "singleton" sensors or form networks with other NLRs to facilitate protein-protein interactions and downstream signaling. The NLRP3 inflammasome, for example, is activated by various triggers and plays a crucial role in innate immune responses and disease. Mutations in NLRP3 can lead to inflammatory disorders, while therapeutic targeting of NLRP3 has shown promise in treating inflammatory diseases. Other NLRs, such as NLRC4, also have significant roles in disease and are potential therapeutic targets.Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of cytosolic pattern recognition receptors that detect pathogenic and sterile triggers. Upon activation, specific NLRs initiate pro- or anti-inflammatory signaling cascades and form inflammasomes, which induce caspase-1 activation to drive inflammatory cytokine maturation and pyroptosis. Certain NLRs and inflammasomes also form PANoptosomes, driving another form of lytic cell death, PANoptosis. This review discusses the evolution, structure, and function of NLR subfamilies in health and disease, highlighting their roles in driving cell death and immunity. Understanding NLR networks may provide therapeutic strategies for infectious and inflammatory diseases and cancer. The NLR family is diverse, with at least 23 members in humans and 34 in mice, and they have evolved to recognize distinct microbial components and host-derived damage-associated molecular patterns (DAMPs). NLRs can function as "singleton" sensors or form networks with other NLRs to facilitate protein-protein interactions and downstream signaling. The NLRP3 inflammasome, for example, is activated by various triggers and plays a crucial role in innate immune responses and disease. Mutations in NLRP3 can lead to inflammatory disorders, while therapeutic targeting of NLRP3 has shown promise in treating inflammatory diseases. Other NLRs, such as NLRC4, also have significant roles in disease and are potential therapeutic targets.