Oncogenic proliferative signals are coupled to a variety of growth inhibitory processes. In cultured primary human fibroblasts, for example, ectopic expression of oncogenic Ras or its downstream mediator initiates cellular senescence, the state of irreversible cell cycle arrest, through up-regulation of cyclin-dependent kinase (CDK) inhibitors, such as p16^INK4a. To date, much of our current knowledge of how human p16 ^INK4a gene expression is induced by oncogenic stimuli derives from studies undertaken in cultured primary cells. However, since human p16 ^INK4a gene expression is also induced by tissue culture-imposed stress, it remains unclear whether the induction of human p16 ^INK4a gene expression in tissue-cultured cells truly reflects an anti-cancer process or is an artifact of tissue culture-imposed stress. To eliminate any potential problems arising from tissue culture imposed stress, we have recently developed a bioluminescence imaging (BLI) system for non-invasive and real-time analysis of human p16 ^INK4a gene expression in the context of a living animal. Here, we discuss the molecular mechanisms that direct p16 ^INK4a gene expression in vivo and its potential for tumor suppression.