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Methadone has been known since the beginning of the 20th century. Its use for cancer pain is still controverted. Several articles clearly show the benefit of methadone for cancer pain. We attempted to identify the advantages of use of methadone early on in the course of cancer. Methadone is a very interesting molecule for cancer pain treatment because of anti NMDA, SSRI and opioid actions, lack of active metabolite, and cost. Its benefits must be balanced against the potential drug to drug interactions during treatment initiation and interactions with other drugs when methadone doses are stable. As for all opioids, side effects can appear. Ten studies including 706 patients support the use of methadone as first line opioid treatment: 7 are prospective studies (one double-blind randomized with morphine, 4 randomized controlled with morphine or transdermal fentanyl, two open studies) and 3 are retrospective studies. Seven studies support its ambulatory initiation (3 prospective including 2 controlled studies, and 4 retrospective studies) with a total of 845 patients. Methadone could be used with caution early on in cancer pain management.