Despite the advances and new drug discoveries, the best drug in metastatic colorectal cancer (mcrc) is 5-fluorouracil. This drug is the backbone of FOLFOX and FOLFIRI which are the standard first line cytotoxic regimens in the metastatic setting. The efficacies of these two regimens are equivalent, and the selection of one over the other is largely based on the side effect profile. Bevacizumab is commonly added to each of these regimes in the first line setting. When a patient develops progression of disease on FOLFOX, then treatment with either single agent irinotecan, or FOLFIRI is a typical approach. If FOLFIRI-BEV is used in first line, the FOLFOX is typically given in second line. All patients with metastatic colorectal cancer have their tumor tested for the KRAS mutation in exon 2. If the tumor is KRAS wild-type then either cetuximab or panitumumab, with or without continued irinotecan, may be used. In patients whose tumors are symptomatic, and so requiring a rapid response, cetuximab or panitumumab may be incorporated into second line therapy instead of third line. There are no data supporting the use of cetuximab after progression on panitumumab or vice versa and use of one of these agents after failure on the other is not appropriate. Upon progression on the standard chemotherapies outlined above appropriate patients may be offered participation in a clinical trial. For patients whose tumors are KRAS mutant a clinical trial should be considered upon progression on oxaliplatin and irinotecan-based regimens. New agents and combinations of targeted therapies described below offer promising therapies for patients with both KRAS wild type and mutant tumors. As our molecular knowledge of mcrc advances future therapies will likely tailor an individualized approach based on tumor specific molecular markers.