Multiple organ failure (MOF) emerged 30 years ago and became our research focus. Over the years, we have proposed a series of cartoons that rallied multidisciplinary translational research teams around common themes to generate “win-win” hypotheses that when tested (right or wrong) have advanced our understanding of MOF. MOF has a bimodal trajectory, and the gut plays a role in both trajectories. Early MOF occurs because of excessive proinflammation (ie, systemic inflammatory response syndrome [SIRS]), and early gut ischemia-reperfusion can amplify SIRS and contribute to the early fulminant SIRS-MOF trajectory. Fortunately, most patients survive early SIRS, but some develop excessive anti-inflammation (ie, compensatory anti-inflammatory response syndrome). The gut also plays a role in this late indolent compensatory anti-inflammatory response syndrome–MOF trajectory. Multiple factors cause progressive gut dysfunction such that the gut (an important immunologic organ) worsens compensatory anti-inflammatory response syndrome and becomes the reservoir for pathogens and toxins that cause late sepsis.