Introduction: Since late 1990’s therapy of metastatic colorectal cancer (mCRC) patients has changed considerable, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. With the introduction of more intensified regimens, it has become even more important to identify patients that will benefit from and can tolerate therapy. Furthermore, the increasing understanding of the biology of mCRC has led to the discovery of new potential targets. Therefore, therapy of patients with mCRC has undergone considerable change from ‘one strategy fits all’ towards a more personalized therapy. Areas covered: We present an overview of the recent literature on approved systemic treatment of mCRC however with focus on how the treatment strategy has changed based on clinical and molecular parameters that presently are used routinely in the clinical situation. Expert commentary: The face of treatment of mCRC has changed from ‘one strategy fits all’ to a personalized approach in which both clinical, molecular parameters and the aim of therapy have to be taking into account when planning the optimal treatment strategy for the individual mCRC patient.