Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. Irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients. The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC.