The present article examines how physiological systems impact on affect regulation, social engagement, and cognitive flexibility, three critical factors in psychotherapeutic success. The vagal system, associated with parasympathetic nervous activity and heart rate variability, provides an integration of brain, heart, gut, affective systems, cognitive performance, and social engagement. The author presents Stephen Porges' polyvagal theory, Julian Thayer's neurovisceral integration model, Kerstin Uvnas-Moberg's oxytocin/hormonal model, and Paul Gilbert's compassion focused therapy, as models for understanding the impact of vagal function and parasympathetic nervous activation on affect, social behavior, and cognition. The article proposes that direct heart rate variability training, along with other practices that increase vagal activity, can prepare patients for psychotherapy, and contribute to progress in psychotherapy. The emphasis is on the reciprocal influences among vagal activity, prefrontal cortical circuits, affect regulation, caring, and thinking.