The clinical importance of high density lipoproteins has grown in recent years with demonstrations of their impact on diverse pathological mechanisms implicated not only in vascular disease, but also in other physiological systems. This is related to the multiple functions associated with high-density lipoproteins (HDL), notably their ability to limit oxidant and inflammatory processes, which are common to different disease states. A second feature of particular clinical relevance is the possibility of synthesising a simplified form of HDL that exhibits some of the functions of the mature lipoprotein. The therapeutic potential of synthetic HDL is already under clinical scrutiny. To illustrate these points, the present chapter will discuss the role of HDL in limiting damage to the heart consequent to myocardial ischemia. It will review molecular survival pathways stimulated by HDL to combat oxidative stress and the potential of synthetic HDL to activate such pathways.