Despite advances in psychopharmacology over the past several decades, treatment outcomes for depression have not substantially improved. Depression is not being eradicated. If anything, the evidence suggests that the problem of depression and treatment-resistant depression is growing, not shrinking. As biologically reductionistic approaches dominate psychiatric practice, patient care has steered away from considering the potent effects of meaning and relationships in the psychopharmacologic treatment of our patients. By construing patients as passive recipients of concrete, specific, and straightforward medical interventions, the field has succumbed to a delusion of precision, and unwittingly moved into an era of treatment resistance in which some of our most potent tools are wasted. In such a model we have settled for treating a disorder rather than a whole person. This article is intended as a step toward remedy. Meaning effects, therapeutic alliance, ambivalence, and patient autonomy, among others, have a powerful and measurable impact on the use of medication that should be considered if we are to treat the whole person. Bringing these elements together into a coherent model of treatment, however, is only a starting point. More research is needed if we are to understand the effects these elements have when used together in an integrated model that is simultaneously personalized and evidence-based.