One of the most influential theories has conceived unexpected panic attack (PA) as a primal defensive reaction to threat within the internal milieu of the body. This theory is based on findings suggesting the involvement of dysfunctional respiratory regulation and/or abnormally sensitive central neural network of carbon dioxide (CO2)/hydrogen ion (H+) chemoreception in PA. Thus, unexpected PA may be related to phylogenetically older brain structures, including the brainstem areas, which process basic functions related to the organism's internal milieu. The brainstem represents a crucial area for homeostatic regulation, including chemoreception and cardio-respiratory control. In addition, the midbrain dorsal periaqueductal gray may be involved in the unconditioned defense reactions to proximal threats, including internal physical stimuli. Our aim was to specifically consider the potential involvement of the brainstem in panic disorder (PD) by a comprehensive review of the available neuroimaging studies. Available data are limited and potentially affected by several limitations. However, preliminary evidence of a role of the brainstem in PD can be found and, secondly, the brainstem serotonergic system seems to be involved in panic modulation with indications of both altered serotonergic receptors and 5-HT transporter bindings. In conclusion, our review suggests that the brainstem may be involved in psychopathology of PD and supports the relevant role of subcortical serotonergic system in panic pathogenesis.