Over the past decades, considerable progress has been made in the management of colorectal cancer (CRC), leading to a significant improvement in overall survival. Although part of this success has been rightly attributed to aggressive surgical management and advances in other adjunct treatments, our understanding of the pathogenesis of CRC and emergence of newer molecular targets for colon cancer has created a powerful impact. In this review article, we will discuss various targeted therapies in the management of metastatic CRC (mCRC). In particular, vascular endothelial growth factor (VEGF)- and epidermal growth factor receptor (EGFR)-targeting monoclonal antibodies have become integral components of the first-line treatment strategies for mCRC. Newer agents on the horizon soon to be incorporated in clinical practice will be briefly reviewed as well. Currently, the only predictive biomarker for treatment selection in patients with mCRC is tumor RAS mutational status.