Since the introduction of behavioral medicine in the early 70s, cognitive-behavioral treatment interventions for chronic pain have expanded considerably. It is now well established that these interventions are effective in reducing the enormous suffering that patients with chronic pain have to bear. In addition, these interventions have potential economic benefits in that they appear to be cost-effective as well. Despite these achievements, there is still room for improvement. First, there is a substantial proportion of patients who do not appear to benefit from treatment interventions available. Second, although the effect sizes of most cognitive-behavioral treatments for chronic pain are comparable to those in psychopathology, they are quite modest. Third, there is little evidence for differential outcomes for different treatment methods. Fourth, there still is relatively little known about the specific biobehavioral mechanisms that lead to chronic pain and pain disability. One direction is to better match treatment programs to patients' characteristics. This can be done according to an "Aptitude X Treatment Interaction" framework, or from the perspective of the Moderator-Mediator distinction. In this introduction to the special series on what works for whom in cognitive-behavioral treatments for chronic pain, we review existing knowledge concerning both moderating and mediating variables in cognitive-behavioral treatments for chronic pain. We further argue in favor of theory-driven research as the only way to define specific a priori hypotheses about which patient-treatment interactions to expect. We also argue that replicated single-participant studies, with appropriate statistics, are likely to enhance new developments in this clinical research area.