The nucleotide-binding oligomerization domain (NOD)-like receptor, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are evolutionarily conserved intracellular sensors critical for detecting pathogen- and damage-associated signals. As key mediators of innate immunity, NLRs orchestrate cellular responses through the assembly of higher-order signaling complexes. In humans, NLRs are central to initiating pyroptosis via inflammasome formation and caspase activation. Comparative studies across kingdoms reveal that although plant and bacterial NLRs do not form inflammasomes, they assemble analogous structures such as resistosomes and antiviral complexes, underscoring conserved principles of supramolecular immune signaling. This chapter provides a structural and mechanistic overview of representative NLRs in human, plant, and bacterial systems, highlighting their roles in immune surveillance and regulated cell death.