β-Adrenergic receptor hyporesponsiveness has been observed in psoriasis and after exposure of epidermis to phorbol esters. It was the purpose of our studies to determine if forskolin, which is known to act synergistically with receptor agonists in elevating endogenous levels of cyclic AMP, could return these responses to those seen under control conditions. It was observed that topical application of phorbol ester to mouse ears in vivo led to a significant reduction in isoproterenol stimulation of cyclic AMP in vitro. Low doses of forskolin (10-7M) were able to enhance isoproterenol’s effect under these conditions. Similarly, human keratinocyte cell cultures treated with phorbol esters and human psoriatic epidermis in vitro were both hyporesponsive to isoproterenol. Again, pretreatment of these samples with forskolin restored the β-agonist stimulation to control values. These data indicate that forskolin is still able to act synergistically with β-agonists in hyporesponsive systems and suggest that forskolin may be a useful probe in defining the mechanism of this decreased responsiveness both in phorbol-ester-treated skin and in psoriasis.