Heat shock proteins (Hsps) are ubiquitously expressed and highly conserved families of molecules, immune reactivity to which has been implicated in the pathogenesis of inflammatory conditions such as autoimmune and cardiovascular disease. The observations that Hsp expression is induced by ischemia-reperfusion injury and is elevated in transplanted organs, and that rejecting allografts are infiltrated by Hsp-specific lymphocyte populations have prompted the suggestions that Hsps and the development of anti-Hsp immune reactivity drive transplant rejection responses. However, although these proteins can activate innate immune cells such as monocytes, macrophages and dendritic cells and can promote the development of proinflammatory immune responses, they are also cytoprotective and have been shown to improve organ viability and function after ischemia-reperfusion injury in a number of experimental models. In addition, the induction of immunity to Hsp60, Hsp70 and Grp78 attenuates experimental autoimmune disease and the induction of immunity to Hsp60 prolongs murine skin allograft survival. It would, therefore, appear that the expression of Hsps and the presence of Hsp-specific lymphocyte populations are not necessarily indicative of a deleterious response; indeed they might reflect an anti-inflammatory, protective response. This chapter reviews current knowledge in the area of Hsps, anti-Hsp reactivity and allograft rejection.