Neuroticism—the tendency to experience negative emotions, along with the perception that the world is filled with stressful, unmanageable challenges—is strongly associated with anxiety, depression, and other common mental health conditions. This state-of-the-art work shows how targeting this trait in psychotherapy can benefit a broad range of clients and reduce the need for disorder-specific interventions. The authors describe and illustrate evidence-based therapies that address neuroticism directly, including their own Unified Protocol for transdiagnostic treatment. They examine how neuroticism develops and is maintained, its relation to psychopathology, and implications for how psychological disorders are classified and diagnosed.