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MHC class I molecules bind and present endogenously loaded peptides to immune effector cells, such as natural killer (NK) cells and T cells. Cell stress, including infection and neoplasia, alters the peptides presented to immune effectors by MHC class I. Cell stress additionally results in the induction of heat-shock proteins (HSPs). Based on observations of multiple researchers, we propose that class I presented-peptide epitopes derived from HSPs are a recognition point for innate and adaptive immune responses. HSPs are rich sources of MHC peptides, and the expression of these peptides increases as a result of several cellular stresses, including viral infection. Functionally, several groups have now confirmed the recognition of HSP peptides by cytotoxic T lymphocytes during both viral infection and tumorigenesis. Similarly, NK cells recognize an HSP60-derived peptide presented by HLA-E. These HSP60–HLA-E complexes lead to NK-cell activation, promoting lysis of stressed cells by members of the innate immune response. This peptide-epitope function of HSPs enables these proteins to act as broad sensors of cellular stress to both the innate and adaptive immune response. [Copyright &y& Elsevier]