This article emphasizes the central role of tumor-based testing for microsatellite instability followed by performance of genetic counselor-driven germline mutation testing in hereditary nonpolyposis colorectal cancer (HNPCC). Suitably aggressive colorectal neoplasm surveillance is shown to be critical. Limitations of the evidentiary base for extracolonic screening are conceded, with some cautious suggestions for possible strategies notwithstanding the lack of data. Advances in chemoprevention have been made in both familial adenomatous polyposis (clinical trial data favoring eicosapentaenoic acid) and HNPCC (controversial aspirin data). For various reasons, however, no agent or combination of agents has yet come into routine use in either condition, with further trials underway or being designed for both conditions.