A proliferation of new cytotoxic and biologic agents has led to improved survival in patients with metastatic colorectal cancer (mCRC). The ability of surgery to increase long-term survival in patients with liver and/or lung metastases also has been firmly established. It has become increasingly difficult as the numbers and types of treatment options have expanded to identify optimal drug combinations, sequences, and duration and the best way to integrate systemic chemotherapy with potentially curative surgery for metastatic lesions. For this review, the authors examined how recent clinical trials have addressed some pertinent questions regarding the use of systemic chemotherapy and biologic agents in patients with mCRC.