In this conceptual paper, we outline the many challenges on the road to personalized psychotherapy, using the example of cognitive behavior therapy (CBT) for depression. To optimize psychotherapy for the individual patient, we need to find out how therapy works (identification of mechanisms of change) and for whom it works (identification of moderators). To date, psychotherapy research has not resulted in compelling evidence for or against common or specific factors that have been proposed as mechanisms of change. Our central proposition is that we need to combine the "how does it work?"-question with the "for whom does it work?"-question in order to advance the field. We introduce the that emphasizes the links and distinction between individual patient differences, therapeutic procedures and therapy processes as a paradigm to facilitate und understand the concept of personalized psychotherapy. We review the mechanism of change literature for CBT for depression to see what we have learned so far, and describe preliminary observational evidence supporting the personalized causal pathway hypothesis. We then propose a research agenda to push the ball forward: exploratory studies into the links between individual differences, therapeutic procedures, therapy processes and outcome that constitute a potential causal pathway, making use of experience sampling, network theory, observer ratings of therapy sessions, and moderated mediation analysis; testing and isolation of CBT procedures in experiments; and testing identified causal pathways of change as part of a personalized CBT package against regular CBT, in order to advance the application of personalized psychotherapy.