Abstract Gut ischemia and reperfusion (I/R) has been implicated as a prime mechanism in the pathogenesis of multiple organ failure and in initiating remote organ failure. Although it has long been known that gut I/R elicits liver dysfunction, only recently has the kinetics of leukocyte accumulation in the hepatic microcirculation and mechanisms of the liver injury after gut I/R been investigated. These studies reveal that the magnitude of gut I/R-induced liver injury depends on the duration of ischemic period and animal species. Gut I/R-induced accumulation of leukocytes, both neutrophils and lymphocytes, in the liver results in an oxidative stress in proximity to non-perfused sinusoid that contributes to subsequent hepatocellular injury. The gut I/R-induced leukosequestration in the liver is mediated by adhesion molecules that are induced by different cytokines, endotoxin, and oxidants. Kupffer cells also play an important role in the gut I/R-induced leukosequestration and liver injury. Nitric oxide and anti-oxidants such as superoxide dismutase protect the liver against the deleterious effects of gut I/R. Furthermore, agents such as ethanol can alter the hepatic responses to gut I/R. The results of these studies provide novel information and potential therapeutic strategies for reducing the liver dysfunction and multiple organ failure induced by gut I/R.