Colorectal cancers develop as a consequence of genomic instability. Microsatellite instability is involved in the genesis of about 15% of sporadic colorectal cancers and in most hereditary non-polyposis cancers. High frequency MSI[1] has been associated with a favorable prognosis, however it is not clear whether this is because MSI-H[2] tumors are inherently less aggressive or because they are more sensitive to chemotherapy. Chemotherapy with a combination of 5-fluorouracil and leukovorin or levamizole has been the standard of care for high risk stage II and stage III CRC[3]; it is also used in stage IV CRC. Several in vitro studies have shown that colon cancer cell lines displaying MSI-H are less responsive to fluorouracil than microsatellite-stable cell lines. Human studies, all of them retrospective, yielded conflicting results. The selection of patients with CRC for 5-FU[4] treatment has been based so far on the stage of tumor rather than the biology of the tumor. Although surgical staging is highly predictive of survival, there are indications that the form of genomic instability within a patient’s colorectal tumor has clinical implications, with and without 5-FU treatment. This review suggests that patients with MSI-H colorectal tumors may not benefit from 5-FU-based chemotherapy and can avoid its potential side effects (nausea, diarrhea, stomatitis, dermatitis, alopecia, and neurologic symptoms) that occur in half the treated patients. If confirmed by future prospective randomized controlled studies, these findings would indicate that microsatellite-instability testing should be conducted routinely and the results used to direct rational adjuvant chemotherapy in colon cancer.