Interruption of blood flow to the liver is an unavoidable consequence of liver transplantation and resectional surgery. A growing body of experimental evidence suggests that reperfusion of the ischemic liver initiates hepatocellular injury and inflammation culminating in severe liver injury and organ dysfunction that may necessitate retransplantation. A large number of studies have implicated reactive oxygen species as potential mediators of this post-ischemic tissue injury. Recent developments in genetic engineering as well as chemical modeling have allowed for the production of novel superoxide dismutase (SOD) isoforms and low molecular weight SOD mimics with extended circulating half-lives or significant membrane permeabilities, respectively. Application of these newly developed free radical scavengers have shown promising results in animal models of liver I/R and may become powerful tools in the treatment of post-ischemic liver injury.