Gene mutations acquired during colorectal carcinogenesis remain drivers of cancer progression in the metastatic setting. KRAS and NRAS mutations define a population refractory to anti-epidermal growth factor receptor (EGFR) antibodies, either as single agents or in combination with standard chemotherapy. High-sensitivity extended RAS testing is currently a requirement to select anti-EGFR therapy irrespective of treatment line, thus limiting unnecessary exposure and expense in patients unlikely to respond. Multiple genetic alterations driving resistance to anti-EGFR monoclonal antibodies have been described, with significant overlap in primary and acquired resistance mechanisms, in line with a clonal selection process. Some of them have been validated as targets for therapeutic intervention in clinical trials, such as ERBB2 amplifications. With advances in drug development and better understanding of the dynamics of target inhibition, additional gene alterations are now promising positive predictive markers for matched targeted therapies in CRC, including BRAF V600E and RNF43 mutations. Furthermore, the microsatellite instable hypermutated colorectal cancer population is particularly sensitive to immune checkpoint inhibitors. In this article, we review the expanding landscape of druggable gene alterations in metastatic colorectal cancer.