To underscore the potential importance of such differences between natural steroid and dexamethasone, it should be noted that dexamethasone protects adrenalectomized mice in the D-galactosamine model, even though endogenous glucocorticoids again appear in effective in defense. Studies with several mouse-sensitization models support the concept that endogenous glucocorticoids are vitally important to general host defense against endotoxin-mediated lethality. The observation that either adrenalectomy or hypophysectomy will markedly sensitize mice to the lethal effects of endotoxin, coupled with the observation that glucocorticoid administration to animals can confer a measure of protection against endotoxin, particularly when given with a pretreatment period, has long been used in support of the concept that glucocorticoids are important to host defense against endotoxin. Studies with several mouse-sensitization models support the concept that endogenous glucocorticoids are vitally important to general host defense against endotoxin-mediated lethality. In the case of the D-galactosamine model, however, dexamethasone may be expected to protect against lipopolysaccharide but not directly against tumor necrosis factor challenge.