The inflammatory response provides an absolutely essential host defense mechanism that, if perturbed, can itself cause a large number of human diseases. Collectively, innate immune responses integrate a number of genome-encoded sensor proteins to combat threats such as pathogens and endogenous damage. Selected throughout multicellular evolution, these proteins recognize patterns of pathogen-specific molecules, such as bacterial flagellin and lipopolysaccharide, with remarkable sensitivity and selectivity. Following detection, host cells launch coordinated defensive measures through innate immune signaling pathways. Two such inflammasome sensors, NLRP1 and CARD8, express highly in skin and lymphocytes and activate in response to a myriad of signals that trigger their functional degradation. Here, we aim to extend our surprising biological findings (unpublished) to novel NLRP1 and CARD8 inflammasome regulators, PREP and PREP-L, whose functions themselves are poorly delineated. Elucidating the molecular basis of their function in inflammation will open new therapeutic windows in inflammatory diseases.