A previously unrecognized pharmacological event, acute tolerance to the vasoconstrictive action of topically applied glucocorticosteroids, has been discovered in human skin. Thus, potent topical glucocorticosteroids will cause vasoconstriction when first applied to human skin but with subsequent applications the production of vasoconstriction rapidly diminishes. However, after a rest period of a few days, the same initial vasoconstrictive effect may be produced again, but this will also disappear if the steroid is again continued topically. These observations have important applications to optimum timing in the clinical topical use of glucocorticosteroids for maximum therapeutic advantage.