The new biologic drugs that are active in the advanced setting of colon cancer have failed when used in the adjuvant setting. Both bevacizumab (NSABP C-08, AVANT-trial) and cetuximab (NO147 trial) added to oxaliplatin-based chemotherapy demonstrated no improvements in 3-year DFS compared with chemotherapy alone. However, subgroup analysis of the NO147 trial indicated that irinotecan and cetuximab might have a synergistic effect and the combination of FOLFIRI and cetuximab led to an improvement in 3-year DFS and 2-year OS compared with FOLFIRI alone. The encouraging results of this small patient cohort have to be confirmed by prospective trials. The use of adjuvant chemotherapy in stage II colon cancer remains controversial. Fluoropyrimidine-based chemotherapy should be discussed in high-risk stage II patients. The addition of oxaliplatin to fluoropyrimidine shows a trend toward improvement in DFS and OS at 5 years in patients with high-risk stage II colon cancer. In our opinion, this combination should be applied only in exceptional cases such as younger patients with accumulation of risk factors. Prognostic classifier like ColoPrint might identify high-risk patients who will benefit from chemotherapy on the basis of gene expression information in the primary tumor.