Elevated cyclooxygenase-2 (COX-2) expression is observed in a variety of premalignant neoplastic tissues, suggesting COX-2 expression might serve as a potential indicator of subsequent tumor development. However, it has not been possible to compare the relationship between Cox-2 gene expression in premalignant lesions and their subsequent fate, because conventional studies require tissue destruction for analysis of gene expression. To monitor COX-2 expression non-invasively during tumor development, we created a Cox-2 luciferase knock-in mouse, Cox-2(luc), in which the firefly luciferase coding region replaces the Cox-2 coding region. Luciferase activity was non-invasively, quantitatively and repeatedly monitored in Cox-2(luc/+) mice subjected to DMBA/TPA multistage skin tumor induction. Luciferase activity is significantly higher in all papillomas than in surrounding skin. However, the magnitude of Cox-2 promoter-driven luciferase activity in small papillomas cannot predict subsequent papilloma regression or growth. Elevated Cox-2 promoter-driven luciferase signal can be detected when papillomas first become visible, but not before this time.