The medical treatment of patients with metastatic colorectal cancer (mCRC) has evolved greatly in the past 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of the targeted monoclonal antibodies bevacizumab, cetuximab, and panitumumab in the treatment of patients with mCRC is now well-established, but the optimal timing of their use requires careful consideration in order to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and epidermal growth factor receptor-targeted biologic agents (cetuximab and panitumumab) in the treatment of patients with mCRC. This article reviews the evidence in support of modern treatments for mCRC and the decision making behind the treatment choices as well as their benefits and toxicities. An evidence-based algorithm is proposed that incorporates the use of these biologic agents early in the treatment of patients with initially nonresectable mCRC based on clearly defined tumor-related factors dependent on the immediate treatment goal. Real-world application of this algorithm is dependent on an individual countries' approval of access to new biologic agents. ; Timothy J. Price, Niall C. Tebbutt, Christos S. Karapetis, Eva Segelov, Nick Pavlakis, David Cunningham, Alberto F. Sobrero, Daniel G. Halle and Jeremy D. Shapiro