Colorectal adenocarcinoma remains the best studied model of gastrointestinal cancer metastases in which in the clinical arena patients may achieve satisfactory long‑term disease free outcomes with a multimodality approach. Predilection for both liver and peritoneal metastasis development is supportive of the long‑held “seed and soil” hypothesis for spread of cancer metastases. This observation has been exploited to treat metastatic disease with locoregional in addition to systemic cytotoxic and molecularly targeted therapies discussed herein. This chapter will also review locoregional modalities for liver metastases such as surgery, radiation, hepatic arterial chemotherapy delivery, radioembolization, and ablative strategies. In addition, the current clinical literature for cytoreductive surgery and regionally‑directed heated intraperitoneal chemotherapy for peritoneal disease will be discussed. Molecular profiling of colorectal cancer is being applied with increasing frequency in the care of colorectal cancer patients and includes defining of CpG island methylator status, microsatellite instability, and KRAS and BRAF gene mutation status. The goal of this review is to motivate laboratory researchers to establish novel preclinical models of colon cancer metastasis that may allow for the more rapid identification of molecular markers or profiles to develop increasingly effective therapies to address or prevent metastatic disease. This may also allow for the more intelligent application of currently available multimodality treatments.