A number of heat shock proteins, or stress proteins, have been shown functionally as potent 'tumor rejection antigens', despite the fact that there are no single tumor-specific mutations in these proteins. Current studies have solved many aspects of this puzzle biochemically and immunologically. The proposal that heat shock proteins are not antigenic per se, but chaperone and present antigenic peptides to MHC class I molecules for recognition by T lymphocytes, has been mechanistically defined. This significance of this discovery is elaborated in the context of the importance of MHC molecules. The immunological principle and the practical vaccination strategy of the two major mammalian heat shock proteins, gp96/grp94 and hsp70 are discussed. It is also argued that extracellular heat shock proteins signal cell stress and tissue damage, and are involved in presenting peptides to the MHC class I pathway through professional antigen presenting cells. These results and ideas form the basis of a new generation of T-cell vaccines against tumors and intracellular organisms.