The authors explore the phenomenon of treatment resistance in relation to medications. They also propose and define a discipline of “psychodynamic psychopharmacology,” describe its philosophical underpinnings and make technical recommendations for the psychodynamic treatment of pharmacologic treatment resistance. The authors review the recent literature suggesting a major role for interpersonal and meaning effects in positive pharmacologic treatment outcomes, and suggest that many patients are “treatment-resistant” to medications because an appreciation of the patient's dynamics is not incorporated into an understanding of repeated treatment failures. Common resistances to the effects of medications are considered, as well as ways that patients may become entrenched in treatment resistant illness from counter-therapeutic uses of medications. The authors propose that psychodynamic psychopharmacology advances the overall clinical effectiveness of medications with treatment-resistant patients by integrating a psychodynamic appreciation of the patient with a psychopharmacologic understanding.