Colorectal cancer is a common malignancy in the United States and a significant cause of mortality yearly. Most recently, target-directed therapies have been added to the armamentarium. These include agents directed at the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). These agents improve survival in some patients; however, they are associated with high costs and increased toxicities. It is, therefore, necessary for a biomarker to be developed to enrich the patient population receiving these agents. Numerous potential biomarkers have been investigated including EGFR copy number, EGFR mutations, PTEN, AKT, KRAS, and the development of the acneiform rash. Here we review the data on KRAS mutation status and the response to treatment of patients with metastatic colorectal cancer (mCRC). These patients have received the EGFR-directed agents, cetuximab and panitumumab. In addition, a cost analysis is also performed to determine the cost effectiveness of KRAS mutation analysis.