Intracellular NOD-like receptor (NLR) proteins are believed to play important roles in innate immune detection or immune regulation, but only a few NLR proteins are functionally defined. Recent intensive studies, largely in vitro, on NLRC5 reveal multiple and controversial roles of this NLR protein in signaling regulation of both innate and adaptive immune responses. Using independently generated Nlrc5-deficient mice, two studies have now established the physiological function of NLRC5 in transcriptional control of MHC class I molecules despite that its role in innate immune signaling remains to be further clarified.