Selection of third-line treatment in metastatic colorectal cancer depends on the agents that have been used in prior therapy. A principle in treatment is to use all five of the active drugs in this setting (5-fluorouracil [5-FU], oxaliplatin, irinotecan, cetuximab, and bevacizumab) during the patient's overall treatment course for metastatic disease because cumulative use of available active drugs appears to increase overall survival. Currently, 5-FU/leucovorin (5-FU/LV)/oxaliplatin (FOLFOX) or 5-FU/LV plus irinotecan (FOLFIRI) can be considered standard therapy in first-line treatment, with cross-over irinotecan or oxaliplatin-containing regimens as a component of several possible second-line regimens. On this scenario, third-line treatment can include the combination of irinotecan with cetuximab or bevacizumab or both or the use of cetuximab and bevacizumab in combination. Data from randomized trials on third-line treatment are needed.