The medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.