Metastatic colorectal cancer (CRC) represents an important health problem in which several biological predictive and prognostic factors have been identified, including clinical features and molecular markers that might influence the response to treatment. Actually, certain prognostic factors are considered key elements, along with disease extent, for deciding the therapeutic approach. However, a distinction between resectable/potentially resectable and unresectable patients must be made in order to establish an adequate therapeutic strategy. Different drugs and chemotherapy regimens are currently available, and their administration depends on patient characteristics, disease-related factors and the treatment objective. Moreover, special situations such as peritoneal carcinomatosis and local treatment of CRC in the setting of metastatic disease should be considered when deciding the most appropriate treatment strategy. This article reviews all the previously mentioned issues involved in the management of metastatic CRC and suggests some general recommendations for its treatment.