Treating depression will remain a mainstay of psychiatric practice. No treatment fits everyone no matter how skillfully applied. Anything as complicated and pervasive as depression, which, as we know, appears as a universal symptom as well as specific syndromes, can only be seen as having multiple contributing variables. Explanatory models include evolutionary ones in addition to the those we regularly think about in the spheres of endowment and experience. When it comes to treating disorders like depression, there will always be people who need to understand who they are in the present in terms of the experiences they have had in the past. For many such people, treatment that is too formulaic or ritualized does not make sense to them and does not work. For most patients, open-ended exploration of origins of problems leads nowhere. Psychodynamic therapy applied in a focused fashion, combined, if necessary, with other approaches including medication, offers many patients the opportunity to put demons to rest. Success in treatment often hinges on a good fit of patient, psychiatrist, and treatment approach. Having flexibility in choosing and applying the treatment that best meets the patient’s needs is ideal.