Failure to properly fold polypeptides into the appropriate three-dimensional structure impacts directly on the ability to synthesize useful proteins and introduces a measure of inefficiency into the cells economy. But protein malfolding has an additional consequence that is unrelated to the lack of properly folded polypeptides but is rather mediated by the presence of malfolded ones. Numerous genetic and biochemical observations suggest that structures elaborated by polypeptides that fail to attain their proper three dimensional fold may exert a deleterious effect on cellular function. This process, also referred to as “proteotoxicity”, appears to be particularly important to the fate of non-renewable cells of long-lived organisms in which accumulating malfolded proteins can exert their deleterious effects over extended periods of time. The progressive aging of the human population has led to an increase in the incidence of diseases hypothesized to be associated with various forms of proteotoxicity. The long-term goal of our research is to identify new components of the cellular response to proteotoxic stress and to integrate these into an understanding of pathophysiology of common human diseases. We expect that our basic research program into the biochemistry, cell biology and genetics of the cellular response to proteotoxins will contribute to the scaffold upon which translational research can later build to create pharmacological tools to manipulate the responses to favorable ends.