Tumor promotion is an essential process in multistage cancer development providing the conditions for clonal expansion and genetic instability of preneoplastic and premalignant cells. It is caused by a continuous disturbance of cellular signal transduction that results in an overstimulation of metabolic pathways along which mediators of cell proliferation and inflammation as well as genotoxic by-products are generated. Among such pathways the oxidative metabolism of arachidonic acid has turned out to be of utmost importance in tumor promotion. The aberrant overexpression of cyclooxygenase-2, an inducible enzyme of prostanoid synthesis and lipid peroxidation, is a characteristic feature of more than two-thirds of all human neoplasias, and the specific inhibition of this enzyme has been found to have a substantial chemopreventive effect in both animal models and man. The prostaglandins produced by COX-2 promote tumor development by stimulating cell proliferation and angiogenesis and by suppressing programmed cell death and immune defense. In mice, a COX-2 transgene fused with the keratin 5 promoter, which is constitutively active in the basal (proliferative) compartment of stratified and simple epithelia, causes a preneoplastic and premalignant phenotype in several organs. Among these organs, skin, mammary gland, urinary bladder, and pancreas have been investigated in more detail. Histologically and biochemically, the COX-2-dependent alterations resemble an autopromoted state that--as shown for skin and urinary bladder--strongly sensitizes the tissue for carcinogenesis. In transgenic animals COX-2 expression is not restricted to keratin 5-positive cells but is seen also in adjacent keratin 5-negative cells. This spreading of the COX-2 signal indicates a paracrine mechanism of autoamplification. While cancer chemoprevention by COX-2 inhibition is a rapidly developing field, much less is known about other pathways of unsaturated fatty acid metabolism, although some of them may play a role in carcinogenesis rivaling that of prostaglandin formation. Here an urgent demand for systematic research exists.