SummaryThe NOD‐like receptor family pyrin domain containing 6 (NLRP6), a member of the NOD‐like receptor (NLR) family, acts as a cytosolic innate immune sensor that recognizes microbe‐associated molecular patterns. In some circumstances upon activation, NLRP6 recruits the adaptor apoptosis‐associated speck‐like protein (ASC) and the inflammatory caspase‐1 or caspase‐11 to form an inflammasome, which mediates the maturation and secretion of the pro‐inflammatory cytokines IL‐18 and IL‐1β. In other contexts, NLRP6 can exert its function in an inflammasome‐independent manner. Tight regulation of the NLRP6 inflammasome is critical in maintaining tissue homeostasis, while improper inflammasome activation may contribute to the development of multiple diseases. In intestinal epithelial cells, the NLRP6 inflammasome is suggested to play a role in regulating gut microbiome composition, goblet cell function and related susceptibility to gastrointestinal inflammatory, infectious and neoplastic diseases. Additionally, NLRP6 may regulate extra‐intestinal diseases. In this review, we summarize current knowledge on the NLRP6 inflammasome and its activation and regulation patterns, as well as its effector functions contributing to disease modulation. We discuss current challenges in NLRP6 research and future prospects in harnessing its function into potential human interventions.