Despite recent advances in the treatment of metastatic colorectal cancer (CRC), the prognosis of patients with this malignancy remains poor. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. Numerous proteins have been implicated as having a crucial role in CRC. There are different targets according to their cellular localization such as membrane receptor targets, intracellular signaling targets, and other protein kinases that regulate cell division. Emerging data from the clinical development of new drugs directed to these targets are providing novel opportunities in the treatment of patients with CRC that will probably translate into an efficacy advantage in the years to come. In this article, we review the current developmental status of some of the most advanced targeted therapies in the treatment of CRC.