To dampen proteotoxic stresses and maintain protein homeostasis, organisms possess a stress-responsive molecular machinery that detects and neutralizes protein damage. A prominent feature of stressed cells is the increased synthesis of heat shock proteins (Hsps) that aid in the refolding of misfolded peptides and restrain protein aggregation. Transcriptional activation of the heat shock response is orchestrated by heat shock factor 1 (HSF1), which rapidly translocates to hsp genes and induces their expression. Although the role of HSF1 in protecting cells and organisms against severe stress insults is well established, many aspects of how HSF1 senses qualitatively and quantitatively different forms of stresses have remained poorly understood. Moreover, recent discoveries that HSF1 controls life span have prompted new ways of thinking about an old transcription factor. Here, we review the established role of HSF1 in counteracting cell stress and prospect the role of HSF1 as a regulator of disease states and aging.