Clinical research of the borderline personality disorder can be difficult and challenging for the investigator. The core psychopathology and characteristic defense mechanisms of the borderline research subject often make the completion of research protocols with these patients problematic. The researcher may also be plagued by issues of ‘classical’ and ‘total’ countertransference. Psychopharmacologic investigations are especially likely to bring these issues to the forefront. Some of the psychologic challenges in completing research with the borderline patient, with special emphasis on psychopharmacologic investigations, are reviewed.