Despite providing a clinically significant survival benefit to patients with metastatic KRAS WT CRC, acquired resistance to the anti-EGFR mAbs cetuximab and panitumumab can arise via three predominant mechanisms: (1) genetic alterations involving downstream EGFR effectors, including KRAS, (2) activation of parallel receptor tyrosine kinase pathways, including HER2 and c-MET and (3) mutations in the extracellular domain of EGFR33. The gene discussed is KRAS; the disease is colorectal carcinoma.