As our understanding of the biology of colorectal cancer evolves rapidly, we are getting closer to identifying the patients with earlier stages of disease, which should benefit and receive adjuvant chemotherapy. Conversely and as importantly, which patients may be spared the toxicities of treatment. 80% of patients with stage II colon cancers will be cured by surgery alone and approximately 20% will relapse. This setting is thus the best clinical illustration of the problem we have to face daily in the clinic, particularly as the clinical benefit to treatment is relatively modest. The survival benefit of Adjuvant 5-fluorouracil chemotherapy for patients with stage II colon cancer is about 2% to 3% at 5 years (corresponding to a 14% to 18% relative risk reduction for death). Can we accurately identify subgroups of patients with stage II disease who will benefit more or less from adjuvant therapy? Novel molecular tests and gene expression–based assays are now commercially available and claim to provide independent clinical value in patients with stage II colon cancer. The relative merit of utilizing these tests will be discussed with the current clinical evidence. These findings may ultimately be applicable to subgroups of stage III disease, and indeed ultimately lead to a novel classification system of risk/benefit.