Colorectal cancer is a significant healthcare problem in the United States, with meaningful improvement in survival over the past few years. Much of that improvement is attributable to the availability of molecularly targeted therapies, such as inhibitors of the vascular endothelial growth factor (bevacizumab) and epidermal growth factor receptor (cetuximab and panitumumab), in addition to active cytotoxic agents. KRAS mutations have long been described to play an adverse prognostic role in colorectal cancer. KRAS is downstream from EGFR, and oncogenic mutations will yield a constitutively active protein that will override EGFR control of downstream signaling. Such mutations in KRAS would therefore confer resistance to anti-EGFR antibodies. The cumulative results of several trials incorporating more than a thousand patients in studies of cetuximab and panitumumab confirm that the presence of KRAS mutation in tumors is highly predictive of resistance to anti-EGFR therapy. These findings are likely to change the landscape of metastatic CRC treatment by providing an improved patient-tailored approach.