The liver is the most common site of metastases in patients with colorectal cancer (CRC), and hepatic metastases are responsible for fatalities in at least two thirds of patients with colorectal malignancy. However, the only available treatment associated with long-term survival in patients with CRC metastases is liver resection. While recent studies have shown that liver resection achieves a 5-year overall survival from 37% to 58%, only 10% to 20% of patients with colorectal liver metastases are eligible for resection. Pharmacologic developments and conceptual advances in chemotherapy, regional treatment, and aggressive surgical strategies have ultimately changed the current treatment of patients with primary unresectable liver metastases caused by CRC. Patients who were treated by only palliative chemotherapy a few years ago presently have a variety of strategies available to render their disease surgically resectable with the potential for long-term survival. These advances are the result of a strong collaboration between medical oncologists and surgeons. The development of new chemotherapy protocols that offer the potential for curative surgery with optimum timing within the natural history of this metastatic disease is a shared therapeutic challenge.