Colorectal cancer is the third most frequently diagnosed cancer, and the fourth leading cause of cancer death in the world [1]. Colon cancer incidence is rising in some parts of the world, especially in Asia. Mortality from colon cancer has decreased over the past 30 years, partly due to better treatment modalities. Approximately 40% of patients diagnosed with colorectal cancer will develop colorectal metastases. In our experience two thirds of these patients have synchronous metastases. Most of the remaining third, who have metachronous metastases, will have received adjuvant therapy based on fluoropyrimidine with or without oxaliplatin. As patients previously exposed to these drugs may still have sensitive tumours, this can influence the management of these patients. The prognosis of patients with metastatic colorectal cancer (MCRC) has been improving in recent years, from a median survival of 12 months or less when 5-fluorouracil was the only available drug to more than 2 years with new drugs and optimal management. In addition to fluoropyrimidines, oxaliplatin and irinotecan are the cornerstones of chemotherapy, while bevacizumab, a monoclonal antibody targeting angiogenesis, and cetuximab or panitumumab, both monoclonal antibodies targeting EGFR, are now available in many countries. Several other factors may also explain the prolonged survival: careful follow-up of patients after curative surgery of the primary cancer, allowing an earlier diagnostic of metastases; increasing use of chemotherapy in the growing elderly population − median age of patients with colon cancer is above 71 years; and surgery of metastases, even in those patients with initially unresectable metastases, when chemotherapy induces a notable tumour shrinkage [2,3]. Two essential parts of the global management of MCRC will be discussed in this paper: the concept of lines of therapy and the re-challenge of a previously administered treatment. Due to the availability of several drugs, multiple regimens have been developed in the treatment of MCRC. These regimens are more active than fluoropyrimidines alone and have no cross-resistance, meaning that patients whose tumours have become resistant to the initial regimen may still be sensitive to another regimen. The concept of lines of therapy is defining the best sequence using different regimens and also the most efficient approach between an “aggressive strategy” using more than two drugs front-line − thus limiting the number of possible lines − and a “conservative strategy” allowing administration of more therapeutic lines. The goal of the aggressive strategy is to increase as much as possible the initial duration of disease control and the response rate, to improve the metastasis resection rate, while the goal of the conservative strategy is to control the tumour growth with safer regimens. The potential drawbacks of the aggressive strategy are more toxicity and a limitation of the rescue options when the tumour has become resistant; those of the conservative strategy are less possible surgical rescue and potentially less patients able to receive all available drugs as tumour progression and comorbidities may not allow the administration of a drug at a late stage. Re-challenge or reintroduction of a previously administered treatment is also a growing part of the management of MCRC. This new approach is driven by two different reasons. The first one is the cumulative toxicity of drugs like oxaliplatin. Most patients are forced to stop oxaliplatin, not for acquired tumour resistance, but for a cumulative neurosensory toxicity. Thus the full potential of oxaliplatin-based therapy is not achieved if patients are treated until neurotoxicity. While this neuropathy is at least partially reversible, the time needed, usually more than 6 months, is not compatible with reintroduction in most patients as second-line therapy does not control the tumour