Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.