One hypothesis for tumor promotion proposes that promoters function to stimulate proliferation of initiated cell populations which produce either: (1) clonal selection of progressing cells; or (2) increased probability of gene rearrangements or fixation of DNA damage. Recent work in our laboratory suggests that the promoting activity of phorbol esters in JB6 mouse epidermal cells is not due to a release from the quiescence type of mitogenic stimulation by the tumor promoter. This conclusion derives from two lines of evidence. First, when JB6 cells are exposed to a promoter under conditions in which they cannot undergo promoter-dependent mitogenesis, promotion of tumor cell phenotype is not inhibited. Second, variants of promotable JB6 cells which have been selected for resistance to the mitogenic activity of the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate (TPA) have been found to retain promotability, thus ruling out mitogenic stimulation as a required event in promotion of transformation in JB6 cells. These TPA mitogen-resistant variants are currently being used to discover biochemical events which determine the mitogenic response. Two such events which appear to mediate the mitogenic response to TPA are EGF (or other growth factor) binding to EGF receptors and stimulated hexose transport.