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Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. During their illness, at least 70% of patients will experience pain sufficiently severe to require chronic opioid treatment. Moreover, Breakthrough Pain (BTP) consists in transitory exacerbations of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy. An inadequate baseline therapy with opioids can be one of the causes of BTP. We will examine the molecular issues that influence the response of patients to opioids. Finally, we will discuss about the importance of individualizing therapy.