The advent of highly effective antipanic medications with specific serotonin reuptake inhibition as a mechanism of action has prompted the need for new pathophysiological models of panic disorder. The authors attempt an integration of the emerging basic science literature regarding the neuro-anatomy and physiology of the mammalian central serotonin nervous system, its influence on neural substrates that underlie fear and defense responses, and the clinical literature pertaining to serotonin-related abnormalities in panic disorder. A neuro-anatomical model for the potential sites of action of the specific serotonin reuptake inhibitors in panic disorder is proposed.