Exposure of cells to environmental and physiological stress leads to an imbalance in protein metabolism, which challenges the cell to respond rapidly and precisely to the deleterious effects of stress on protein homoeostasis. The heat-shock response, through activation of heat-shock transcription factors (HSFs) and the elevated expression of heat-shock proteins and molecular chaperones, protects the cell against the accumulation of non-native proteins. Activation of HSF1 involves a complex multi-step pathway in which the inert monomer oligomerizes to a DNA-binding, transcriptionally active, trimer which relocalizes within the the nucleus to form stress-induced HSF1 granules. Attenuation of the heat-shock response involves molecular chaperones which repress the HSF1 transactivation domain and HSF-binding protein 1 (HSBP1), which interacts with the HSF1 oligomerization domain of HSF1 to negatively regulate its activity, thus insuring that the expression of chaperones is precisely determined.