Control of pain has a central role in patients treatment either in advanced cancer or other terminal illnesses and in acute postsurgical or chronic non-malignant diseases. Hospitals should promote programs of research on genetic mechanism, and also biochemical and physiological aspects of pain through highly specialized labs. Opioids are the first choice drugs for moderate to severe chronic pain, especially at the end of life, and among them oral morphine is worldwide recognized by the World Health Organization and by the European Association for Palliative Care as the conventional therapy. Although this general agreement, administration of this class of drugs may be a major medical challenge due to the high effects' variability related to pharmacokinetic and pharmacodynamic parameters, such as absorption, distribution and metabolism, as well as intrinsic efficacy at the receptors involved. For such a reason, optimization of the management regime is not always reached in all the patients. Up to now no one can easily predict which patient will experience side effects or an inadequate pain control. The growing body of evidence concerning a sound genetic background of this human intervariability has prompted research on the field of a personalized therapy, focusing on single nucleotide polymorphisms (SNPs), being the most common and diffuse form of genetic variation. This review has the main goal to report the most promising human genetic polymorphisms involved in opioid treatment, and address the relationship between these polymorphisms and the clinical outcome.