Despite a decrease in incidence and mortality, colorectal cancer (CRC) still represents the second leading cause of cancer worldwide. Recurrence following surgery and adjuvant treatment and the metastatic disease are still a major problem with a median overall survival of approximately 24 months. Nevertheless, there has been an improvement in outcome due to the introduction into clinical practice of new cytotoxic and targeted agents. The targeted agents that have improved the efficacy of the available chemotherapeutic regimens in CRC are the ones that target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). In particular, bevacizumab, a recombinant humanized monoclonal antibody against VEGF, cetuximab, and panitumumab, two monoclonal antibodies that target the EGFR, have been approved for the treatment of metastatic CRC (mCRC). While for anti-EGFR agents, predictive biomarkers have been found, no good biomarkers have been found yet for anti-VEGF agents. Aflibercept and regorafenib have recently also been approved in patients with mCRC. This article reviews in an extensive way the data of large randomized clinical trials for the use of anti-VEGF and anti-EGFR in CRC. Aim of this review is also to describe the current status of biomarkers discovery and highlight how to improve the therapeutic index of these targeted agents by selecting in advance the subgroup of patients who will benefit from these treatments.