Topical administration of the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), is accompanied by an increased incorporation of [3H]arachidonic acid into mouse skin and a very significant activation of epidermal cell membrane phospholipase A2 without affecting intracellular acid phospholipase. Similar enhancement in epidermal cell phospholipase A2 was observed after application of phorbol-12,13-didecanoate or 3-methylcholanthrene to mouse skin. A small but significant increase in phospholipase A2 activity is also seen after application of the nonpromoter irritant, acetic acid. The elevated levels of the prostaglandins observed in mouse skin after topical application of promoters are probably triggered by the activation of this membrane enzyme.