Cyclooxygenase-2 (COX-2) is a highly inducible enzyme exerting diverse actions on cell functions, including proliferation, migration, and DNA damage. Enhanced COX-2 expression may be protective, but excessive expression may be harmful, causing inflammation, atheromatous plaque instability, and intimal hyperplasia. COX-2 transcriptional activation by proinflammatory mediators has been extensively characterized. In this review, the role of C/EBP in regulating COX-2 transcription is highlighted. Recent advances in control of COX-2 transcription by aspirin and salicylate and by a cell cycle-dependent endogenous mechanism are described. The recent progress sheds light on the pathophysiological mechanisms of COX-2 and new transcription-based strategy for controlling COX-2 overexpression and COX-2-mediated cardiovascular diseases.