C OX-2 promotes colon cancer. While both nonselective NSAIDs and selective COX-2 inhibitors reduce disease burden, their adverse gastrointestinal and cardiovascular side effects limit their therapeutic use. In this issue of the JCI, Zhang et al. used gene silencing and a derivative of licorice root to show that inhibition of the enzyme 11β–hydroxysteroid dehydrogenase type II (11βHSD2) reduces tumor COX-2 activity, tumor growth, and metastasis by increasing the tonic glucocorticoid-mediated suppression of the COX-2 signaling pathway without the adverse effects associated with NSAIDs and selective COX-2 inhibitors (see the related article beginning on page 876). Their findings suggest that 11βHSD2 inhibition may be a potential therapeutic option in colon cancer, warranting further investigation.