The role of antiangiogenic and anti-epidermal growth factor receptor (EGFR) agents has been investigated extensively in colorectal cancer in the palliative, adjuvant, and neoadjuvant settings. Although the role of biologic agents has become well-defined in the first, second, and subsequent lines of treatment of metastatic colorectal cancer (mCRC), considerable debate continues around the optimal sequencing and around optimal patient selection. The benefits from integrating bevacizumab or cetuximab in the adjuvant setting have been investigated in several randomized phase III clinical trials in stage II/III disease, all with disappointing results. Neoadjuvant approaches incorporating biologic therapy in patients with liver metastatic disease have led to mixed results. Although the current evidence does suggest increased down-staging and increased resectability with the addition of cetuximab in patients with initially unresectable or borderline resectable liver metastases, a positive effect of anti-EGFR therapy on the overall survival (OS) in this setting is not conclusive. Patients with resectable liver metastases derive no benefit and may experience potential harm from the addition of cetuximab to neoadjuvant chemotherapy. Similarly, there is neither rationale nor adequate data to support the addition of bevacizumab to neoadjuvant chemotherapy in patients with resectable liver metastases. In this review, we examine the role of antiangiogenesis and anti-EGFR therapies across the spectrum of adjuvant, neoadjuvant, and metastatic disease.