The heat shock response, a primitive and highly conserved cellular defense mechanism, has broad protective effects against sepsis-induced injury. In various models of sepsis, induction of the heat shock response protects against sepsis-induced mortality, organ injury, cardiovascular dysfunction, and apoptosis. The mechanisms by which the heat shock response protects against sepsis-induced injury are currently under investigation. One potential mechanism involves the ability of the heat shock response to inhibit proinflammatory responses. The heat shock response has been demonstrated to inhibit expression of the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. The heat shock response has also been demonstrated to inhibit cytokine-mediated expression of inducible nitric oxide synthase. Recent studies demonstrated that the heat shock response inhibits nuclear translocation of nuclear factor-kappaB (NF-kappaB), a transcription factor involved in the regulation of many proinflammatory responses. Heat shock response-mediated inhibition of NF-kappaB nuclear translocation involves stabilization of an NF-kappaB inhibitory protein called I-kappaBalpha. The heat shock response also increases expression of I-kappaBalpha, thus providing another potential mechanism by which the heat shock response can modulate proinflammatory responses. Future studies designed to further understand the protective role of the heat shock response against sepsis-induced injury may allow for the development of rational pharmacologic agents or gene therapy methods to safely induce the heat shock response as a strategy to treat patients with sepsis.