Recent insights into the molecular pathogenesis of colorectal cancer have given rise to specific target-directed therapies, including monoclonal antibodies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These drugs have been approved as second and third line therapies for metastatic colorectal cancer (mCRC). Activating mutations of the K-Ras family of genes are the most common genetic events in tumorigenesis and have been implicated as a predictive factor in determining response to anti-EGFR drugs in pivotal studies. Phase II and III trials, conducted for investigating the role of K-Ras status on anti-EGFR treatment, revealed that patients with wild-type K-Ras had better clinical response in terms of prolonged median progression-free survival and overall response rates when compared to mutant K-Ras. In contrast, patients with mCRC benefit from anti-VEGF treatment irrespective of K-Ras status. Interestingly, a combination of anti-EGFR and anti-VEGF demonstrates no added value in these patients. The studies concluded that pretreatment testing of K-Ras in patients with mCRC offers valuable information in deciding treatment options. There are several molecular methods for mutation detection that seem practical enough to apply in clinical practice. Further confirmatory prospective studies are needed to evaluate the role of K-Ras mutation detections in tumor metastases, early stage CRC, and method of sampling specimens.