Metastatic colorectal cancer is a major cause of cancer-related mortality. Surgical resection of all known metastatic disease can be curative in selected patients. The majority of patients, however, require the consideration of systemic chemotherapy as optimal palliative treatment for their diseases. Using new effective chemotherapeutic agents such as irinotecan and oxaliplatin has resulted in a clear and clinically significant improvement in survival for patients with metastatic colorectal cancer. The optimal sequences and combinations of these agents as initial and salvage chemotherapy along with 5-fluorouracil (5-FU) and leucovorin are controversial. It seems clear that it is important for all patients to have access to all 3 drugs at some point in their therapy for optimal results. Recent randomized trials of first-line chemotherapy for metastatic colorectal cancer in which patients were likely to have access to all 3 effective drugs demonstrated median survivals of 18-20 months. This compares favorably to median survivals of approximately 12 months for patients treated with 5-FU-based regimens alone prior to the availability of effective salvage therapy. A small but meaningful number of patients might develop resectable disease with curative intent as the result of significant tumor response to combination chemotherapy. Herein, we review recent developments in combination and sequential chemotherapy for metastatic colorectal cancer and the implications for the optimal treatment in these patients.