Cancer is a public health problem worldwide and a major cause of death or disability. Pain is one of the most common and feared symptoms in patients with cancer with marked impact on quality of life. According to the WHO analgesic ladder, opioids are the mainstay of cancer pain management, if well-accepted guidelines are systematically applied. Oral morphine has been widely used in treating cancer pain of moderate to severe intensity and remains the preferred first choice to many clinicians for its familiarity/availability/costs. However, a significant proportion of patients under oral morphine do not have successful outcomes, often switched to alternative strong opioids. Opioid rotation is a therapeutic maneuver aiming in improving analgesic response and/or reducing adverse effects, including change to different medication using the same administration route, maintaining the current medication but altering administration route, or both. In this review, a detailed presentation of the available literature, regarding opioid rotation strategy, up to now is performed. Indications, principles, opioid dose-conversion recommendations, and guidelines in oncology patients are presented. An outline of the evidence supporting the use of this therapeutic modality on clinical benefit/outcome is attempted. Mechanisms contributing to patients' variable opioid response are underlined. Since 1/3 of population will die from cancer (80 percent with severe pain in their final year of life) effective pain control remains an ongoing challenge. Opioid rotation may be useful in opening the therapeutic window and establishing a more advantageous analgesia/toxicity relationship. However, too much work is to be done to further individualize analgesic therapy for patients with cancer.