Nitric oxide biology has provided the impetus for the development of anticancer agents based on their ability to release NO. The so called NO-donating NSAIDs (NO-NSAIDs) are emerging as a prototypical members of this class of compounds for the chemoprevention of cancer. They consist of a conventional NSAID to which a NO-releasing moiety is covalently attached. Recent progress in their preclinical and mechanistic evaluation has unraveled their cardinal features. Compared to their parent compounds, NO-NSAIDs are up to several hundred times more potent in inhibiting the growth of colon cancer cell lines and also quite effective in preventing colon cancer in various tumor animal models of colon and pancreatic cancer. A strong cell kinetic effect, including inhibition of proliferation, induction of cell death, and inhibition of cell cycle phase transitions underlines their chemopreventive effect. NO-aspirin (NO-ASA) ids the NO-NSAID best studied mechanistically. The induction of oxidative stress appears crucial for its anticancer activity. Major effects have been identified on various cell signaling pathways including Wnt, NOS2, MAPK and Nrf2 signaling. Perhaps paradoxically, NO-ASA induces the expression of COX-2 while inhibiting cell growth strongly. NO-NSAIDs, particularly NO-ASA, appear to be very safe compounds, as evidenced from many animal and early human studies. An ongoing clinical trial is designed to determine whether NO-ASA can inhibit early stages of colon carcinogenesis in subjects at risk for colon cancer.