NOD-like receptor family pyrin domain containing 6 (NLRP6) is a novel NLR family member, that shows high expression in the intestine and liver (in contrast to NLRP3 in myeloid cells), to regulate inflammation and host defense against microbes. NLRP6 is reported to involved in inflammasome activation, regulation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, antiviral interferon (IFN) signaling, mucus secretion, and antimicrobial peptide (AMP) production. Here, we discuss the recent findings as well as debates regarding: how NLRP6 is induced ("signal I″) and activated ("signal II"); its roles in intestinal cells and immune cells; how NLRP6 and NLRP9 coordinate to regulate the anti-viral immune response in the intestine; potential targeting of NLRP6 in human diseases.