The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risks for esophageal, gastric and colon cancers as well as other solid tumors. The antitumor effect of NSAIDs is mediated through cyclooxygenase-2 (COX-2)-dependent and -independent regulation of oncogenic and tumor-suppressive pathways. Recent discoveries have shed new light on the regulation of COX-2 at the molecular level in these cancers. Moreover, prostaglandin E 2 (PGE 2), a COX-2-derived eicosanoid, has been found to affect numerous tumorigenic processes. In this connection, PGE 2 activates multiple intracellular signaling pathways, including (1) transactivation of epidermal growth factor receptor (EGFR); (2) protein kinase C-dependent, EGFR-independent activation of extracellular signal-regulated kinase (ERK) and the transcription factors activator protein-1 and c-Myc; (3) G-protein-mediated activation of β-catenin/TCF-dependent transcription. Activation of these signaling pathways by PGE 2 is mediated by EP receptors whose inhibitors suppress gastrointestinal carcinogenesis. Taken together, COX-2 expression is dysregulated in many types of cancer and COX-2-derived PGE 2 elicits multiple oncogenic signals to promote carcinogenesis. Targeting PGE 2 signaling by EP receptor antagonists holds promise for the development of targeted therapy for the treatment of cancer.