A causal association between inflammation and cancer has long been suspected. Multiple lines of compelling evidence from clinical, epidemiologic and laboratory studies support that inflammation plays a critical role in the promotion and progression stages of carcinogenesis. Recent progress in our understanding of the molecular biology of cancer highlights the intracellular signal transduction network, including that involved in mediating the inflammatory response, which often functions abnormally during carcinogenesis. One of the key players in inflammatory signaling is cyclooxygenase-2 (COX-2). Aberrant upregulation of COX-2 is frequently observed in various precancerous and malignant tissues. Pro-inflammatory stimuli trigger the activation of an intracellular signal transduction network comprising proline-directed serine/threonine kinases, and their downstream transcription factors, resulting in an inappropriate induction of COX-2. Therefore, the normalization of inappropriately overamplified signaling cascades implicated in chronic inflammation-associated carcinogenesis by use of COX-2 specific inhibitors has been recognized as a rational and pragmatic strategy in molecular target-based cancer prevention. This review highlights the cancer preventive effects of some anti-inflammatory phytochemicals derived from edible plants, and their underlying molecular mechanisms with a focus on representative transcription factors and upstream kinases responsible for COX-2 induction.