Some of the most significant therapeutic advances in the treatment of cancer have occurred in the management of colorectal metastases. The introduction of new cytotoxic chemotherapeutic and biologic agents has changed the approach to these patients from both an oncologic and a surgical perspective. In addition, an understanding of the molecular mechanisms by which these agents affect tumors is developing. This molecular information will be critical in the future in designing therapeutic regimens based on an individual tumor's genetic profile rather than treatment for a specific tumor type. The rapidly evolving treatment of colon cancer has provided several interesting genetic biomarkers/pathways/genes-/kinases that have been targeted or seem to play an important role. Of particular interest is the blockade of epidermal growth factor receptor (EGFR) with monoclonal antibodies. This treatment is efficacious when used alone or combined with chemotherapy. However, recent data revealed that patients with tumors positive for the K-ras mutation do not benefit from EGFR blockade. Compelling evidence has indicated that mutated K-ras is an important oncogene involved at the early stage of the development of colorectal cancer. Furthermore, mutations in the K-ras gene have been associated with aggressive tumor biology. K-ras mutational analysis is an important step in the overarching goal of developing personalized medicine. New treatment strategies are needed to more effectively treat patients with the K-ras mutation.