There is a wealth of experimental, epidemiological, and most recently, randomized trial evidence that suggests that aspirin and other NSAIDs can reduce the risk of colorectal adenoma and cancer. As a result, these medications have emerged as promising chemopreventative agents. However, routine use has not been recommended in large part due to a lack of information on the optimal dose and duration of treatment. In this issue, observational data drawn from a cohort within the Polyp Prevention Trial strongly support the effectiveness of aspirin and NSAIDs in reducing the risk of recurrent colorectal adenoma, including those with morphologically or histologically advanced features. In particular, the investigators demonstrate that participants who consumed more than one standard aspirin tablet per day had the greatest reduction in risk. Because much potential toxicity of these agents are dose-related, these findings highlight the need for further investigation into the optimal dose and duration of the medications before consideration of their use in widespread chemoprevention efforts. The combination of future epidemiological data, in concert with continuing experimental developments, will guide further research initiatives and better inform cost-benefit and decision analyses. Hopefully, interpretation of this large body of evidence ultimately will lead to concrete clinical guidelines which will define a role, if any, for these medications as anticancer agents.