Substantial progress has been achieved in the management of metastatic colorectal cancer (mCRC) over the last two decades. The overall survival has increased from 10 months to more than 30 months. These improvements are due to the integration of multiple cytotoxic agents and targeted therapies, as well as individualized treatment strategies using molecular and clinical factors. More specific, molecular characteristics such as RAS mutation status and clinical factors such as performance status, tumor burden, tumor-related symptoms and comorbidities are crucial in selecting treatment strategies. Here I review the landscape of cytotoxic chemotherapy for mCRC, regional chemotherapy strategies to accumulate cytotoxics within the tumor and reflect on future directions for treatment of mCRC.