Collaborative empiricism, which involves a systemic process of therapist and patient working together to establish common goals in treatment, has been found to be one of the primary change agents in cognitive-behavioral therapy (CBT). This article focuses on the development of a therapeutic relationship and implementation of collaborative empiricism along with the elements that lead to success in treatment. This method is used to uncover patients’ automatic thoughts and underlying beliefs in treating an array of emotional and behavioral disorders. The role of the therapist is discussed in developing, promoting, and maintaining therapeutic collaboration and what is constituted by the empirical process. A case study illustrates the use of collaborative empiricism with a patient suffering from panic disorder. The article concludes with a series of clinical practices that will enhance collaborative empiricism and collaboration in CBT, and thereby treatment outcomes.