Living cells are continually challenged by conditions which cause acute and chronic stress. To adapt to environmental changes and survive different types of injuries, eukaryotic cells have evolved networks of different responses which detect and control diverse forms of stress. One of these responses, known as the heat shock response, has attracted a great deal of attention as a universal fundamental mechanism necessary for cell survival under a variety of unfavorable conditions. In mammalian cells, the induction of the heat shock response requires the activation and translocation to the nucleus of one or more heat shock transcription factors which control the expression of a specific set of genes encoding cytoprotective heat shock proteins. The discovery that the heat shock response is turned on under several pathological conditions and contributes to establish a cytoprotective state in a variety of human diseases, including ischemia, inflammation, and infection, has opened new perspectives in medicine and pharmacology, as molecules activating this defense mechanism appear as possible candidates for novel cytoprotective drugs. This article focuses on the regulation and function of the heat shock response in mammalian cells and discusses the molecular mechanisms involved in its activation by stress and bioactive cyclopentenone prostanoids, as well as its interaction with nuclear factor kappaB, a stress-regulated transcription factor with a pivotal role in inflammation and immunity.