Despite advances made in its understanding and treatment, chronic pain remains an unsolved and all too common problem. One of the main obstacles to successful management of pain is the high variability of many patients regarding both response to treatment and susceptibility to adverse effects, which curtails the utility of therapeutic intervention. Understanding the causes of this variability is an important challenge which may lead to a new era in rational pain management. As described in this review, however, there currently seems to be more than one possible explanation of this variability. Rational personalized pain management must take into consideration both ever-increasing knowledge of pharmacogenetics and pharmacokinetics and a broad, clinically based attitude incorporating co-morbidities, both physical and psychiatric, and concomitant medications. Novel models for testing in-vivo pain processing, for example assessment of conditioned pain modulation (CPM), are also promising approaches to use of rational data for empirical treatment of pain. Last, listening to the patient and understanding the context in which pain has affected his or her life is an important part of maintaining the personal nature of therapeutic interaction with patients suffering from pain.