The primary goal of therapy in acute myocardial infarction is to salvage jeopardized myocardium and preserve left ventricular function (1). Despite the success of contemporary reperfusion strategies, many patients with evolving myocardial infarction sustain extensive myocyte necrosis, resulting in heart failure, arrhythmia, and death. Although early restoration of blood flow to ischemic myocardium reduces infarct size, many patients with acute myocardial infarction present more than 3 h from symptom onset, beyond the timeframe when significant salvage can occur (2–6). Moreover, many patients have suboptimal tissue-level perfusion despite restoration of TIMI-3 grade epicardial flow, as a result of ischemia-induced microvascular injury, distal embolization, and reperfusion injury (7–13). Given that left ventricular function is the most important determinant of long-term survival (1–16), there is a clear need for novel therapies that might protect the myocardium and enhance myocardial salvage. Among newer therapeutic approaches, hyperoxemic reperfusion and hypothermia appear very promising as cardioprotective strategies. This chapter will review several innovative devices used to apply these therapies, experimental data that form the scientific basis for their use, as well as recent developments in clinical investigation.