Nucleotide-binding and oligomerization domain (NOD)-likereceptors(NLRs) are pattern-recognitionreceptorssimilar to toll-likereceptors(TLRs). While TLRs are transmembranereceptors, NLRs are cytoplasmicreceptorsthat play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and variousdiseasesrelated toinfectionandimmunity. NLR studies have recently begun to unveil the roles of NLRs indiseasessuch as gout, cryopyrin-associated periodic fever syndromes, and Crohn'sdisease. As these new associations between NRLs anddiseasesmay improve our understanding ofdiseasepathogenesis and lead to new approaches for the prevention and treatment of suchdiseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role ininfection,immunity, anddisease, particularly from clinical perspectives.