Teleocidin, isolated from mycelia of Streptomyces mediocidicus is a mixture of two teleocidin A isomers with molecular weights of 437 (A-1 and A-2) and four teleocidin B isomers with molecular weights of 451 (B-1, B-2, B-3, and B-4). Previously we found that each purified isomer of teleocidins A and B had approximately the same activity as teleocidin in an irritant test on mouse ear, in inductions of ornithine decarboxylase in mouse skin and adhesion of human promyelocytic leukemia (HL-60) cells, and in inhibition of the specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse skin particulate fraction. This paper reports the strong activation of protein kinase C in vitro by each isomer of teleocidins A and B at a concentration of 1 microgram/ml. Detailed studies on the potent tumor promoting activities of the two teleocidin A isomers and four teleocidin B isomers in a two-stage carcinogenesis experiment on mouse skin are also reported, including histological findings on the tumors. Treatment of mice with 100 micrograms of 7,12-dimethylbenz(a)anthracene and then 2.5 micrograms of any one of the six isomers of teleocidins A and B twice a week induced tumors in 80.0 to 91.7% of the mice with 2.8 to 5.2 tumors/mouse in week 30. Scarcely any tumors developed in groups treated with 7,12-dimethylbenz(a)anthracene or any one of the isomers of teleocidins A or B alone. The percentages of incidences of mice bearing papillomas and carcinomas in the six groups treated with 7,12-dimethylbenz(a)anthracene plus one isomer of teleocidins A or B were 90.9 to 98.3% and 1.7 to 9.1%, respectively. These results indicate that all of the isomers of teleocidins A and B have potent tumor promoting activity on mouse skin, irrespective of the structural differences between teleocidins A-1 and A-2, and among the four isomers of teleocidin B. The structure-activity relationship of teleocidins A and B is discussed on the basis of our recent results. Based on the structures of related compounds, we propose a revised numbering system for compounds of the teleocidin class.