Chronotherapy has consisted in the adaptation of chemotherapeutic drug delivery to circadian (approximately 24-hour) rhythms. This can be achieved in fully ambulatory patients using multichannel programmable pumps. Up to approximately 1500 patients with metastatic colorectal cancer have been registered in one of 15 trials testing the relevance of this treatment method with 5-fluorouracil +/- leucovorin +/- oxaliplatin. Chronotherapy was shown as significantly less toxic and more effective than constant rate infusion in 2 consecutive multicenter trials. High efficacy and good tolerability permitted secondary surgical resection of previously inoperable metastases, with apparent survival improvement (3-year survival > or = 20%) and cures in some patients. This strategy is currently undergoing further testing within the European Organization for Research and Treatment of Cancer. Nevertheless, combining chronotherapy with surgery of colorectal cancer metastases can be readily offered to patients as a safer therapeutic option for optimizing outcome.