I-Ornithine decarboxylase (ODC) is essential for polyamine synthesis and growth in mammalian cells; it provides putrescine that is usually converted into the higher polyamines, spermidine and spermine. Many highly specific and potent inhibitors of ODC are based on the lead compound a-difluoromethylornithine (DFMO), which is an enzyme-activated irreversible inhibitor. DFMO is accepted as a substrate by ODC and is decarboxylated, leading to the formation of a highly reactive species that forms a covalent adduct with either cysteine-360 (90%) or lysine-69 (10%). Both modifications inactivate the enzyme. ODC activity is normally very highly regulated at both transcriptional and post-transcriptional levels according to the growth state of the cell and the intracellular polyamine content. Experimental over-production of ODC can be caused by either transfection with plasmids containing the ODC cDNA with part of the 5'-untranslated region (5'UTR) deleted under the control of a very strong viral promoter, or transfection of plasmids that cause the overproduction of eIF-4E, reported to be a limiting factor in the translation of mRNAs with extensive secondary structures in the 5'UTR. In both cases, unregulated overexpression of ODC transforms NIH 3T3 cells to a neoplastic state. Along with studies showing that many tumor promoters increase ODC activity and that a number of preneoplastic conditions and tumor samples show high levels of ODC, these results suggest that ODC may act as an oncogene in an appropriate background. This provides a rationale for the possible use of ODC inhibitors as chemopreventive agents. Further support comes from studies showing that reducing ODC activity with DFMO abolishes the transformed phenotype of the NIH 3T3 cells overexpressing ODC; many studies found that treatment with DFMO reduces tumor incidence in experimental animals exposed to carcinogens. Although these results provide strong support for initial testing of DFMO as a chemopreventive agent, other means of reducing ODC activity should not be overlooked, including the use of other enzyme-activated irreversible inhibitors with higher potency and/or better pharmacokinetics than DFMO, use of dominant negative mutations or ribzymes to reduce active ODC levels, and use of regulators of ODC expression.