Several molecular pathways have been shown to play key roles in the development and progression of colorectal cancer (CRC). This enhanced understanding of tumor biology has provided the rationale for the design and development of novel agents that are directed against important targets, including growth factors, receptors, and tumor-specific/tumor-selective antigens. The epidermal growth factor receptor (EGFR) signaling pathway has received much attention over the past 5-10 years because it is overexpressed in more than 85% of tumors from patients with metastatic CRC. Cetuximab and panitumumab are monoclonal antibodies presently approved for use by the FDA in the refractory disease setting, and they have provided significant advances in the treatment of advanced CRC. However, much focus has shifted toward using these biologic therapies in combination with cytotoxic chemotherapy in up-front settings, such as first-line therapy and in the neoadjuvant therapy of liver-limited disease. The clinical studies conducted to date suggest that cetuximab can be safely and effectively combined with oxaliplatin- and irinotecan-based chemotherapy in the first-line treatment of metastatic CRC. Moreover, the results of the CRYSTAL phase III study provide support for the use of the combination of FOLFIRI (5-fluorouracil/leucovorin/irinotecan) and cetuximab in the neoadjuvant setting and allow for R0 surgical resection with curative intent. Much work continues to investigate the critical molecular biomarkers that can be used to predict clinical response to chemotherapy and/or targeted therapies as well as to identify which patients might be at increased risk for developing drug-specific side effects.