Injury due to ischemia and reperfusion (I/R) causes an inflammatory response due to oxidative damage, which triggers stress signaling processes that eventually result in cell apoptosis and death. There are a number of chemical mediators and pathways involved in the I/R response. Thus from a therapeutic point of view, it would be most efficient to focus on the most important active mediators of inflammation and apoptosis and manipulate these to improve cell function and survival. Over the last few years, the Akt pathway has become such a target due to its role as a signaling pathway where modulation of substrates prevents apoptosis. The involvement of Akt in the cell survival pathway is a complex process that requires an extensive machinery of intracellular events. The aim of this review is to organize these findings to better understand Akt's mechanism of protection and how it modulates specific substrates in the heart, liver, and brain affected by I/R. Akt functions as a survival kinase by phosphorylating a number of apoptosis-regulatory molecules such as BAD, forkhead transcription factors, caspase 9, and IkappaB kinase to influence NF-kappaB and GSK-3beta. Akt's broad scope places it at the center of multiple critical steps, allowing it to play a protective role in various organs affected by I/R injury. From a practical and clinical application point of view, the upregulation of Akt could potentially be used alone or in combination with other therapeutic strategies to treat I/R injury and thus to improve cell and organ function. The means by which Akt manipulation should occur is not well defined, and it is possible that pharmacologically, such as in the case of selectin inhibitors in our experience or through well-orchestrated gene therapy, this important molecule can be better upregulated and therefore can offer effective protection. The short- and long-term effects with Akt upregulation have not been well studied so far. Early concerns about cancer or cardiac damage potential are inconclusive. Thus, more experiments are required in this particular area of research.