Nonsteroidal antiinflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase-2 (COX-2) induced at sites of inflammation. They are among the most widely used drugs worldwide, but their cardiovascular side effects are a major concern for patients, regulators, and industry. NSAID side effects are mediated by inhibition of constitutively expressed COX-2 present in discrete regions, including the kidney. However, the pathways driving constitutive COX-2 remain poorly understood. The work presented here defines these pathways and importantly shows constitutive COX-2 expression in the kidney occurs through pathways distinct to those driving COX-2 in inflammation. These data therefore highlight the potential that targeting COX-2 at the transcriptional level may provide a way to dissociate antiinflammatory benefits of NSAIDs from their treatment-limiting cardiovascular side effects.