Until recently, heat shock proteins (also known as heat stress proteins) have mostly been regarded as intracellular molecules that mediate a range of essential housekeeping and cytoprotective functions. However, interest in their role as intercellular signalling molecules has been fuelled by the observations that these molecules can be released and are present in the extracellular environment under physiological conditions. They can elicit cytokine production by, and adhesion molecule expression of, a range of cell types, and they can deliver maturation signals and peptides to antigen presenting cells through receptor-mediated interactions. These functions suggest that heat shock proteins could be immunoregulatory agents with potent and widely-applicable therapeutic uses. Furthermore, the induction of self heat shock protein immune reactivity can attenuate autoimmunity and delay transplant rejection, and heat shock proteins derived from tumours and pathogens can elicit specific, protective immunity. This review will focus on this rapidly evolving area of heat shock protein biology.