The thesis of this article is that a case formulation-driven approach to clinical work that relies on a case formulation and a hypothesis-testing approach to each case facilitates the use, in clinical settings, of empirically supported treatments (ESTs) that were developed in research settings. The two touchstones of a case formulation-driven approach to cognitive-behavior therapy (CBT) are, as the title of the article indicates, "mechanism" and "empiricism." In a formulation-driven approach, the therapist relies on hypotheses about the "mechanisms" causing, maintaining, and promoting change in problem behaviors. The therapist also adopts an "empirical" approach to each case that includes hypothesis-testing and repeated data collection to evaluate the process and progress of treatment. This article describes the main features of a case formulation-driven approach to CBT, shows how it addresses many of the obstacles that impede practitioners from using empirically supported protocols in their daily clinical work, examines its intellectual origins and some data supporting its effectiveness, and concludes with a discussion of implications of the method for future developments in the field.