The mouse skin model of multistage carcinogenesis has demonstrated that cancer results from a synergism between genotoxic and nongenotoxic factors. The former induce irreversible genetic alterations, whereas the latter promote tumor development by favoring the clonal outgrowth of the genetically altered cells. While therapeutic gene repair is a still unrealized dream, tumor promotion provides an attractive target for cancer prevention. A key event in epithelial tumor development is an aberrant constitutive overexpression of cyclooxygenase-2 (COX-2), being detectable already in premalignant lesions and leading to an overproduction of prostaglandins. In the mouse skin model, prostaglandin F2alpha has been identified as an endogenous tumor promoter. The well-established chemopreventive effect of nonsteroidal anti-inflammatory drugs seems to be mainly due to COX-2 inhibition. Targeted transgenic overexpression of COX-2 in mouse epidermis induces a preneoplastic phenotype and renders the tissue extremely sensitive to genotoxic carcinogens; i.e., for the induction of skin tumor development, tumor promoter treatment can be omitted in those animals. It is concluded that COX-2 acts as an endogenous tumor promoter and that its overexpression represents a first order risk factor for cancer development. Conversely, specific COX-2 inhibitors rank among the most promising agents for cancer chemoprevention.