For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micro-metastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent to achieve these goals. The a priori molecular identification of patients who could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the targeted therapies up to now available for mCRC) is of critical importance. In this setting, the KRAS mutational status is the first identified predictive marker of response to anti-EGFR therapy and is required prior treatment with anti-EGFR therapy. For KRAS wild-type patients, the choice is in between anti-VEGF and anti-EGFR. In the future, in addition to clinical considerations, molecular markers may provide critical information for selecting patients who might benefit preferentially from one of these drugs. Indeed, the tumor's pathology and patient's metabolism is driven by genetic make-up, influencing the individual response and toxicity. A great amount of exploratory data has been delivered. The challenge of treatments' optimization through specific biomarkers gain special value for a potentially curable disease as mCRC with metastases confined to the liver, and it is even more important if we consider that we do really have the opportunity of mutually exclusive therapeutic choices in this setting. The high degree of complexity of the biological systems we are dealing with makes the discovery of determinant biomarkers a demanding endeavor per se. On the other hand, researchers have to face with all the difficulties of prospective verification and clinical validation of the most promising factors. In the future, to make translational research productive, affordable and more concrete, it will be necessary to have a worldwide effort from the scientific community (from medical oncologists to surgeons and basic researchers, but also of national health systems, industries, regulatory agencies and academies).