The selection of salvage therapy after first-line treatment failure for metastatic colorectal cancer patients has become more complex with the development of several active drugs in this setting. The addition of oxaliplatin and irinotecan to 5-fluorouracil in the first-line therapy has conditioned the election of the regimen used in second-line, becoming a standard of care the switch between both schedules at the time of disease progression. The recent introduction of new targeted drugs has complicated the scenario even more, allowing different possible combinations in first-, second-, third- and even fourth-line therapy. The role of hepatic arterial infusions has been reconsidered with the availability of new and more active cytotoxic drugs and has become an approach to be taken in mind in the management of these patients. With the possibility of active salvage therapy, surgery rescue approaches should be taken in account during all the course of the patients' disease.