The identification of KRAS mutation status as a predictive biomarker for the activity of epidermal growth factor receptor (EGFR) inhibitors in metastatic colorectal cancer has marked a turning point in the use of these agents in the clinic. A wealth of data indicates that patients with wild-type KRAS derive meaningful clinical benefit from cetuximab in first- and second-line settings and beyond, both in combination and as a single agent, and from panitumumab as a single agent in the refractory setting. Patients with KRAS-mutant tumors do not benefit from EGFR inhibition and should not be treated with these agents. KRAS mutation testing should be part of routine standard practice, preferably at the time of diagnosis or early in the course of management. Immediate knowledge of the KRAS mutation status of a tumor allows for the optimal incorporation of anti-EGFR monoclonal antibody (MoAb) therapy where it may be most beneficial for the patient, such as in downstaging regimens outside of the refractory setting where anti-EGFR MoAb therapy is otherwise typically indicated. Available technologies make this test relatively easy to implement; archival paraffin-embedded samples from primary or metastatic sites can be used indistinctly without compromising reliability and without the need for repeated biopsies. Several diagnostic laboratories provide KRAS testing services. This powerful selection tool reduces unnecessary toxicities and costs and should be part of the standard diagnostic workup of any patient.