After nearly 40 years of treatment of metastatic colorectal cancer with 5-fluorouracil (5-FU) or best supportive care, the treatment of this disease has evolved rapidly in the last decade. Treatment options now include several new cytotoxic and biologic agents. Combination regimens, such as folinic acid, 5-FU plus oxaliplatin (FOLFOX), and folinic acid, 5-FU plus irinotecan (FOLFIRI), have significantly improved clinical efficacy as related to response rates and overall survival. The optimum integration of chemotherapy regimens with biological agents targeting critical signaling pathways, such as, bevacizumab (monoclonal antibody targeting VEGF-A), cetuximab and panitumumab (monoclonal antibodies targeting the EGF receptor) are still under evaluation. With the availability of several treatment options, however, comes the issue of optimal duration of chemotherapy in order to achieve the dual goals of clinical efficacy and quality of life, and the issue of cost–effectiveness of treatment, particularly with the newer targeted therapies. One method of achieving this may be to accommodate planned treatment holidays so patients can recover from the physical and psychological side effects of their chemotherapy as long as clinical efficacy is not compromised. In this review, we discuss the evidence for the use of intermittent chemotherapy in metastatic colorectal cancer.