In this article we present an overview of the results of our studies suggesting that endogenous glucocorticoid hormones play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Indomethacin and aspirin at ulcerogenic doses induce a rise in corticosterone, which helps the gastric mucosa to resist the harmful actions of these ulcerogenic agents. The gastroprotective action of glucocorticoids during NSAID treatment may be mediated by multiple actions, including maintenance of glucose homeostatis, mucus production and attenuation of enhanced gastric motility and microvascular permeability. According to our findings, glucocorticoid hormones also participate in the healing processes of NSAID-induced gastric injury. It was demonstrated that there is some cooperative interaction between glucocorticoids and prostaglandins (PGs) in gastroprotection, in a way that a deficiency of one protective factor can lead to an apparently compensatory increase of the other. The gastric mucosa becomes more susceptible to injury during deficiency of both glucocorticoids and PGs.