Members of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family are quickly emerging as critical regulators of innate and adaptive immune responses during microbial infection and autoimmunity. The NLR family member NLRC5 was recently proposed to function as a positive and negative regulator of antiviral immune responses. NLRC5 has also been implicated in regulation of inflammasome signaling and MHC class I transcription. Some of these functions have recently been assessed in NLRC5-deficient mice and immune cells. Here, we summarize and review the newly gained knowledge on the structure, expression profile and putative functions of NLRC5 in regulating immune responses and host defense.