Prokaryotic and eukaryotic cells respond to potentially damaging stimuli such as elevated temperature by increasing the synthesis of a family of proteins collectively known as stress proteins. The major stress proteins (also known as heat shock proteins) are among the most highly conserved and abundant proteins found in nature. Stress proteins have been shown to be among the dominant antigens recognized in immune responses to a broad spectrum of pathogens. Recent reports indicate that immune responses against stress proteins can be highly crossreactive and can even involve anti-self reactivity. Some of these reports implicate immune responses to stress proteins in arthritis. Others suggest that healthy individuals may have the capacity to respond to self stress protein determinants in a manner that could help eliminate their own cells that are infected, transformed, or otherwise stressed. The purpose of this review is to bring together observations on the nature of stress proteins, the antigenicity of stress proteins, and the relationship between stress protein antigens and autoimmunity. The Stress Response and Stress Proteins One to two dozen proteins are induced in response to a range of different stresses, including heat shock, nutrient deprivation, oxygen radicals, and metabolic disruption. The best studied of these stresses is heat shock (reviewed in Lindquist and Craig, 1988), in which a sudden increase in temperature induces the increased synthesis of heat shock proteins (hsp’s). The heat shock response is the most highly conserved genetic system known. Because many of the heat shock proteins are also induced by other stresses, we refer to them here as stress proteins. The stress proteins are remarkable in their evolutionary conservation. For example, the hsp90, hsp70, and hsp60 proteins are found in all prokaryotes and eukaryotes. Pairwise comparison of hsp70 sequences from almost any two organisms reveals that about half of the amino acid residues are identical, and many of the remaining residues are similar. Hsp90 and hsp60 are similarly highly conserved. Indeed, these are among the most highly conserved proteins known.