In critically ill patients, disruption of intestinal epithelial cell function occurs due to exposure of the epithelium to toxic internal and external inflammatory stimuli, which are key factors that trigger sepsis and multi-organ dysfunction syndrome (MODS). A greater understanding of how trauma and gut failure lead to sepsis and progression to MODS is much needed. In this issue of the JCI, Armacki and colleagues identify mechanisms by which thirty-eight-negative kinase 1 (TNK1) promotes the progression from intestinal apoptosis and gut failure to bacterial translocation, sepsis, and MODS. Moreover, the results of this study suggest TNK1 as a potential therapeutic target to prevent sepsis and MODS.