Medicinal treatment of colorectal cancer liver metastases has undergone significant developments in the past two decades. Cytotoxic treatment regimens have demonstrated greater efficacy and contributed to a significant improvement in survival. Perioperative therapy with FOLFOX has demonstrated progression-free survival benefits in resectable colorectal liver metastases in a prospective randomized controlled trial. The safety of perioperative chemotherapy was found to be acceptable and only a few patients showed initial progression. In general, preoperative chemotherapy should not extend beyond 3-4 months to avoid chemotherapy-associated liver damage. For patients with borderline resectable metastases, a response to chemotherapy can establish secondary resectability. Combinations of cytotoxic drugs are adequate in this situation. The addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies for tumors without RAS mutations are reasonable choices for a better response and improved survival outcome. It is crucial that all treatment decisions for systemic colorectal liver metastases include correct definitions of treatment goals and endpoints and are derived based on appropriate multidisciplinary considerations.