Survival rates for metastatic colorectal cancer (CRC) have increased considerably over the years largely because of the application of optimized chemotherapy regimens. More recently, the addition of the targeted agents bevacizumab, cetuximab, and panitumumab in advanced disease has also demonstrated clinical benefit. Adjuvant chemotherapy is the standard of care in patients with early-stage CRC who are at high risk of recurrence. One challenge is how to apply targeted agents in early-stage CRC. Initial results from the NSABP-08 trial in CRC, the first report of bevacizumab in the adjuvant treatment of solid cancers, are disappointing. Nevertheless, the results of several important phase III trials of targeted adjuvant therapy are awaited. Until then, the use of targeted agents in early-stage CRC cannot be recommended. The identification of biomarkers to select patients who might derive clinical benefit is crucial in determining the full potential of targeted agents in the adjuvant setting. In this review, we discuss the biologic rationale for targeted therapies in early-stage CRC, the current clinical trials, and the clinical challenges facing the success of these agents in the adjuvant setting.