AbstractNLRP1, while the first inflammasome described, has only recently begun to gain significant attention in disease pathology, inflammation research, and potentially, as a therapeutic target. Recently identified human variants provide key insights into NLRP1 biology while its unique expression in barrier cells such as keratinocytes and airway epithelial cells has aligned with new, human specific agonists. This differentiates NLRP1 from other inflammasomes such as NLRP3 and identifies it as a key therapeutic target in inflammatory diseases. Indeed, recent discoveries highlight that NLRP1 may be the predominant inflammasome in human barrier cells, its primary role akin to NLRP3, to respond to cellular stress. This review focuses on recent studies identifying new human-specific NLRP1 mechanisms of activation of, gain-of-function human variants and disease, its role in responding to cellular stress, and discuss potential advances and the therapeutic potential for NLRP1.