With the currently available cytotoxic and targeted drugs, metastatic colorectal cancer (mCRC) may be controlled by systemic treatment for a substantial period of time. However, many questions remain about the optimal use of drugs and duration of treatment. The feasibility of chemotherapy-free intervals has been studied in patients with mCRC treated with chemotherapy alone, but the results are conflicting. Current data show that oxaliplatin may be safely interrupted, but they do not allow a firm conclusion on the safety of a full treatment break of chemotherapy. For targeted therapy, continuous inhibition of intracellular signaling by prolonged administration would theoretically be beneficial for efficacy of treatment. Recent data support the use of maintenance treatment with chemotherapy and bevacizumab. No data on the optimal duration of treatment with anti-epidermal growth factor receptor (EGFR) agents are currently available.