Curative resection of liver metastases from colorectal cancer is associated with high 5-year overall survival rates, making complete resection the goal of therapy for many patients. Improved outcomes in recent years have resulted in the application of increasingly aggressive multidisciplinary approaches for patients with metastatic disease. The addition of newer, more active chemotherapeutic regimens has prolonged patient survival in those with advanced disease and increased the number of patients eligible for surgical therapy. Furthermore, integration of chemotherapy with hepatectomy in patients with initially resectable disease offers the potential for improving survival beyond that seen with resection alone. Recent randomized studies have demonstrated a benefit of both adjuvant and neoadjuvant chemotherapy. However, questions regarding the optimal indications, regimen, and sequence of therapy remain. The use of neoadjuvant chemotherapy has potential advantages over postoperative adjuvant therapy, including improved patient selection, determining response to therapy, and achieving earlier delivery of systemic therapy. The disadvantages sometimes seen with neoadjuvant therapy include chemotherapy-associated hepatotoxicity and inability to identify resectable lesions. Ultimately, a therapeutic strategy that includes all aspects of multidisciplinary and multimodality care is required to select and treat this complex group of patients.