Inflammasome complexes are important effectors of innate immune responses, and chronic inflammation in the gut has been linked to tumorigenesis. Zhong et al. have found germline gain-of-function mutations in the gene encoding the inflammasome receptor, NLRP1. These mutations cause two skin disorders that are associated with epidermal hyperplasia and they relieve auto-inhibition of NLRP1 activity such that carriers exhibit spontaneous inflammation.