Simple SummaryColorectal cancer is one of the leading causes of cancer-associated deaths worldwide. From the 1960s to 2002, the standard systemic treatment consisted of cytotoxic chemotherapy. However, in the past 20 years, the development of targeted therapies has revolutionized care for CRC. Dozens of new drugs have been developed specifically targeting actionable and identifiable molecular biomarkers expressed by these tumors. This growing field, precision oncology, has been responsible for a dramatic drop of more than 50% in the CRC mortality rate in the United States. As research into this field exponentially expands, new targets are being uncovered, and new drugs are being developed. This review aims to summarize the recent advances in biomarkers, landmark trials, and future perspectives for colorectal cancer.AbstractIn 2022, approximately 600,000 cancer deaths were expected; more than 50,000 of those deaths would be from colorectal cancer (CRC). The CRC mortality rate in the US has decreased in recent decades, with a 51% drop between 1976 and 2014. This drop is attributed, in part, to the tremendous therapeutic improvements, especially after the 2000s, in addition to increased social awareness regarding risk factors and diagnostic improvement. Five-fluorouracil, irinotecan, capecitabine, and later oxaliplatin were the mainstays of mCRC treatment from the 1960s to 2002. Since then, more than a dozen drugs have been approved for the disease, betting on a new chapter in medicine, precision oncology, which uses patient and tumor characteristics to guide the therapeutic choice. Thus, this review will summarize the current literature on targeted therapies, highlighting the molecular biomarkers involved and their pathways.