Abdominal compartment syndrome (ACS) has emerged to be a significant problem in patients who develop postinjury multiple organ failure (MOF). Current laboratory research suggests that ACS could be a second hit for the development of MOF. Recent studies demonstrate that ACS is an independent predictor of MOF and that the prevention of ACS decreases the incidence of MOF. The Trauma Research Centers at the University of Colorado and the University of Texas-Houston Medical School are focused on defining the role of the gut in postinjury MOF. Because ACS is a plausible modifiable risk factor, our interest has been to 1) describe the epidemiology of ACS, 2) build prediction models, 3) provide strategies for prevention and treatment of ACS, and 4) develop relevant laboratory models. This review summarizes our findings.