The chemoprevention of colon cancer, the second leading cause of cancer-related deaths in the United States, has been pursued actively during the last two decades. Methodological problems and those stemming from the available agents per se have constrained this difficult task; to some extent, these problems persist to date. That NSAIDs decrease the incidence of and mortality from colon cancer has been a major advance in chemoprevention. These compounds are, however, limited by their significant side effects. NO-releasing NSAIDs (NO-NSAIDs) are a novel class of compounds, synthesized to overcome the limitations of NSAIDs. In general, they appear safer and much more effective than their traditional counterparts. We review their structural features, metabolism and pharmacological actions. In vitro and in vivo studies indicate that they are much more effective than traditional NSAIDs in modulating colonocyte kinetics and the formation of premalignant colon lesions. Their mechanism of action is complex and not fully understood, including modulation of NO synthesis, signaling mediated via NF-kappaB and likely other pathways. Current early findings indicate that NO-NSAIDs may play a highly promising role in the chemoprevention of colon cancer.