The defense mechanism of the gastrointestinal mucosa against aggressive factors, such as hydrochloric acid, bile acid and non-steroidal anti-inflammatory drugs, mainly consists of functional, humoral and neuronal factors. Mucus-alkaline secretion, mucosal microcirculation, and motility act as functional factors, while prostaglandins and nitric oxide act as humoral factors, and capsaicin sensitive sensory neurons act as neuronal factors. All the above factors are known to contribute to mucosal protection. In recent years, heat shock proteins (HSPs), to include HSP70, have been implicated to be an additional factor utilized for the defense mechanisms of the gastrointestinal mucosa at the intracellular level. The expression of HSP70 and HSP47 markedly changes during the development and healing of chronic gastric ulcers in rats. It was revealed that HSC70 (a constitutive form of HSP70) is coprecipitated with cyclooxygenase-1 and the neuronal form of nitric oxide synthase after treatment with a mild irritant (20% ethanol). A positive relationship between enhanced interaction of HSC70 with either cyclooxygenase-1 or nitric oxide synthase and mucosal protection against a strong irritant (100% ethanol) was observed. It was concluded that HSPs might contribute to mucosal defense mechanisms and ulcer healing, most probably through protecting key enzymes related to cytoprotection.