To provide guidelines for handling the very labile phorbol ester, RPA,2 its stability under various laboratory conditions was studied. RPA will remain undecomposed for 8 weeks if stock solutions are made in ethanol, ethyl acetate, or DMSO and stored in absolute darkness at -20 degrees C. When exposed to light RPA readily isomerizes to 13'-cis-RPA. Structure/activity investigations of irritant polyfunctional diterpene esters of phorbol, ingenol, and resiniferonol with saturated and unsaturated aliphatic or with aromatic acids indicate that their irritant activity is a necessary, yet insufficient prerequisite for initiation- (or tumor-) promoting activity (e.g., Refs. 3 and 4). For further testing of this hypothesis, the retinoic acid analogue of the mouse skin irritant and initiation-promoter TPA, i.e., RPA, was designed (7). In initiation/promotion experiments of skin of NMRI mice, it proved to be an irritant almost as active as TPA, but only marginally active as a promoter. In combination with TPA, it turned out to be a "second stage" promoter (PII-promoter) (1, 6) in our strain of mice (2, 7). RPA is a much more labile compound than TPA (5), especially in the solid form. If stored in solution, special precautions have to be taken to ascertain that the concentration or dose intended is represented by undecomposed RPA.