The main effects in psychotherapy research have been smaller than expected. Rather than concluding that psychotherapy has weak effects, clinical researchers have argued that average effect sizes are reduced because of mismatches between clients and treatment. Hence, Aptitude X Treatment interaction (ATI) research has been viewed as a promising new frontier in psychotherapy research. If ATI research is to become a productive and progressive program, then researchers will need to focus their attention on interesting and meaningful ATIs. This will require greater theoretical precision and a stronger emphasis on construct validity. Specific issues addressed in this article include Type II and Type III errors, manipulation checks from both the patient and practitioner perspective, considerations of the strength of treatment, the need to test rival hypotheses, and the desirability of collaborative research.