Heat Shock Proteins (HSPs) are intracellular molecular chaperones, which preserve protein folding and protect cells from injury. Intracellularly, their normal location, HSPs are protective. HSPs can also be found in the extracellular compartment, either after necrotic cell death or independent of cell death. The physiologic function of exogenous HSPs remains elusive. However, extracellular as well as membrane- localized HSPs have been implicated in the pathogenesis of a number of diseases including type I diabetes, Crohns, atherosclerosis and juvenile chronic arthritis. It is thought that HSPs can provoke an immune response either by directly activating the innate immune system, or through the adaptive immune response leading to production of antibodies, possibly as a result of prior exposure to the bacterial HSPs, which have great sequence similarity. Extracellular HSPs can activate Toll-like receptors (TLR), and induce the production of cytokines; but, intracellular HSPs can downregulate cytokine production and mediate myocardial protection. Production of nitric oxide may trigger HSPs, ameliorating cardiotoxic effects of cytokines. Apoptosis has come into focus as a contributing factor for ischemia/reperfusion injury, and conflicting data exist about a potentially beneficial or deleterious role of HSPs. Although novel therapeutic strategies include elevation of specific HSPs, the interplay of HSPs in the clinical setting is poorly understood.