Following the first report of tumor promotion by okadaic acid in 1988, we further identified additional tumor promoters of the okadaic acid activity class, such as calyculin A and microcystin-LR. However, tautomycin, which is also an inhibitor of protein phosphatases-1 and -2A (PP-1 and PP-2A), as are okadaic acid, calyculin A and microcystin-LR, is not a tumor promoter on mouse skin or in rat glandular stomach. This paper presents unique features of the okadaic acid activity class of tumor promoters with regards to three significant findings: 1) the okadaic acid pathway, mediated through inhibition of PP-1 and PP-2A, is a general tumor promotion pathway in various organs; 2) simultaneous treatment of okadaic acid with teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA) activity type of tumor promoters, did not show any synergistic effects on tumor promotion; and 3) two different types of tumor promoters, okadaic acid and TPA, commonly induced tumor necrosis factor-α (TNF-α) gene expression on mouse skin. The results also strongly suggest that TNF-α, now known to be an endogenous tumor promoter and a mediator of cancer development, plays an important role in tumor promotion and progression in humans. In the light of this, we discuss a practical method of screening for chemical tumor promoters based on their induction of TNF-α release from HL-60 cells.