Following stimulation of rat epididymal adipose tissue segments with epinephrine, cyclic AMP levels increase to maximum values by 5 min; thereafter, cyclic AMP levels decline, reaching values which may not be significantly different from prestimulation levels. When additional epinephrine was added to the incubation medium or when stimulated tissues were transferredto fresh epinephrine containing media, the anticipated second increase in cyclic AMP was absentor greatly diminished. Addition ot theophylline to the restimulation medium failed to overcome the apparent “refractoriness” to the second epinephrine stimulation. The apparent“refractoriness” to epinephrine stimulation was also induced by prior exposure toACTH but not to theophylline, suggesting that lipolysis per se is not the cause of unresponsiveness. Becausetissues remain unresponsive even when transferred to fresh medium, the “refractoriness” cannot be ascribed to the release of an inhibitory substance into the medium. All epinephrine and theophylline stimulations caused comparable increases in lipolysis not correlated with the magnitude of the increase in cyclic AMP levels. It follows that tissues retain responsiveness to hormones insofar as lipolysis is concerned. Epinephrine induced refractoriness was prevented by exposure of tissues to the anti-lipolytic agents nicotinic acid and prostaglandin E1, but not to imidazole. Because theophylline does not cause “refractoriness” whereas epinephrine and ACTH do, it is suggested that “refractoriness” results from activation of adenylate cyclase. (Endocrinology94: 1372, 1974)