All organisms sense and respond to environmental and physiological stress by inducing cell stress responses that protect core biosynthetic processes such as DNA repair, protein folding, and clearance of damaged proteins. Of these, the heat shock response (HSR) protects the proteome against acute exposure to elevated temperatures, oxidants, and heavy metals, for example, and to the chronic expression of metastable, aggregation-prone proteins associated with aging and diseases of protein conformation. Induction of the HSR leads to the rapid and robust expression of molecular chaperones and other cell-protective pathways to protect nascent chain synthesis and folding, to prevent misfolding and aggregation, and to promote recovery from stress-induced damage. This review examines the properties of the stress-responsive transcription factor, HSF-1, in the regulation of the HSR, our current understanding of the stress-sensing mechanisms that recognize and distinguish between acute stress such as heat shock and chronic proteostasis imbalance as occurs in neurodegenerative diseases, and the cell nonautonomous control of the HSR by neuronal signaling in metazoans. This complex, systems-wide interdependence ensures cellular health span and organismal life span.