It is well known that the presence of personality disorder presents special challenges in the treatment of depression. In this clinical paper, we clarify the interrelationship between personality and depression; and suggest important implications for the psychotherapy and pharmacotherapy of patients who are comorbid with both conditions. Included in our considerations are the impact of genetically based temperament; perfectionism as a personality trait; the introjective and analytic subtypes of depression; and the role of early childhood trauma in altering the biology of the patient and affecting the therapeutic alliance. We used two clinical examples to illustrate the interplay between features of personality and the treatment of depression. We suggest that there is considerable reason for optimism if clinicians can re-conceptualize the challenges presented by these patients. Instead of seeing them as treatment-refractory, they can be regarded as requiring longer duration and different treatment strategies. Copyright © 2007 John Wiley & Sons, Ltd.