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Research indicates that treatment-resistant depression is common in clinical practice. Although there are several reasons why depression can be difficult to ameliorate, one common reason stems from comorbid personality disorders. Research has shown that not only are personality disorders commonly comorbid among those with depression, but their presence negatively affects the course and outcome in the treatment of depression. This implies that careful assessment of comorbid personality pathology is of critical importance in the case conceptualization of treatment-resistant depression and may be essential for planning treatments that most benefit patients. In the following article, we illustrate the value of transference-focused psychotherapy (TFP), an evidence-based approach for treatment of personality disorders, in addressing treatment-resistant depression when there is a comorbid personality disorder. To do this, we discuss the evidence regarding the comorbidity of treatment-resistant depression and personality disorders and the implications for treatment approaches. We make an argument for treatments such as TFP. We then explicate the TFP model of treatment, including TFP's model of personality pathology in the development of treatment-resistant depression. In doing so, we also describe the evidence base behind TFP and its mechanisms of change. Clinical vignettes are also used to give clear examples of how TFP assesses and treats treatment-resistant depression in the context of personality pathology.