Acute postoperative pain is a complex phenomenon that baffles the staff involved in both its prevention and treatment. Acute postoperative pain varies even among patients who underwent the same type of surgery, and it is now known to be caused by different factors, including genetic background. This review will focus on the most important genes correlated with inter-patient differences in both pain sensitivity and analgesic response. Pain therapy is often administered to patients who are also taking other types of medication; therefore, drug interactions must be considered. A genetic analysis of receptors, of drug transporters, and of metabolizing enzymes may be needed to establish the effective doses of each drug in the individual patient to prevent side effects and also to achieve pain relief in a shorter period of time, which may prevent acute pain from becoming chronic. The etiology of chronic pain has not been elucidated yet, but we know that genetic predisposition comes into play, together with other clinical factors. Clinical trials including genetic analysis could be extremely useful in optimizing the management of postoperative pain therapy.