Modern chemotherapy regimens, combining bolus or infused schedules of 5-fluorouracil (5-FU) with irinotecan or oxaliplatin, have significantly improved the treatment outcomes of patients with metastatic colorectal cancer (CRC). The addition of novel targeted agents to chemotherapy has the potential to increase the median survival of patients with metastatic CRC beyond 2 years. Bevacizumab, a monoclonal antibody (mAb) to vascular endothelial growth factor, has an established role in first-line treatment in combination with either 5-FU/leucovorin or irinotecan/5-FU/leucovorin regimens, while cetuximab, a mAb to epidermal growth factor receptor, in combination with irinotecan is more suitable for the treatment of refractory metastatic CRC. The use of bevacizumab in later stages of the disease and cetuximab in chemotherapy-naive patients as well as concurrent treatment with both agents is still under investigation. The landmark studies leading to the approval of these agents in the treatment of metastatic CRC as well as associated toxicity profiles and detailed treatment recommendations are discussed in this review.