Colorectal cancer (CRC) remains a leading cause of cancer death in the developed world. Metastatic disease eventually develops in nearly 50% of patients with CRC. Chemotherapy is the mainstay of treatment in metastatic CRC (mCRC); however the majority of patients remain incurable with current therapeutic options. Progress made in the field of surgery, locoregional treatment for low-volume metastatic disease, and systemic chemotherapy has created new treatment paradigms and improved survival in mCRC. Development of new cytotoxic drugs and the advent of targeted agents over the past decade have seen the median overall survival (OS) for mCRC increase from 9 months to > 2 years. Data from trials integrating targeted therapies appear to indicate that not all have efficacy as single agents and the choice of chemotherapy used in combination with these agents may impact results. Ongoing research is leading to identification of new biomarkers of response, further defining the subpopulations who achieve greatest benefit. Hence optimizing treatment for this group of patients has become increasingly complex, requiring a multidisciplinary approach not only to identify those who are curable with resectable disease but also to determine when it is best to incorporate targeted drugs, with which chemotherapy, and in whom. Currently bevacizumab, cetuximab, and panitumumab are the only approved biologic agents for use in mCRC. In this article we discuss the evidence supporting the use of biologic agents with chemotherapy and suggested strategies for their integration into the treatment armamentarium of mCRC.