This paper will acquaint readers with the pathophysiology that guided the development of anti-EGFR therapies for colorectal cancer and will synthesize the huge amount of clinical data that supports limiting the use of cetuximab and panitumumab alone or in combination with irinotecan as second- or third-line therapy for metastatic colorectal cancer without mutations of the KRAS gene. This evidence concerns the gene KRAS and metastatic colorectal cancer.