Neural circuitry residing within the medullary ventral respiratory column nuclei and dorsal respiratory group interacts with the Kölliker-Fuse and medial parabrachial nuclei to generate the core breathing rhythm and pattern during rest. Triphasic eupnea consists of inspiratory [I], post-inspiratory [post-I], and late-expiratory [E2] phases. Mesencephalic zones exert modulatory influences upon respiratory rhythm-generating circuitry, sympathetic oscillators, and cardiovagal premotoneurons. The earliest evidence supporting the existence of midbrain control of breathing derives from studies conducted by Martin and Booker in 1878. These authors demonstrated electrical stimulation of the deep layers of the mesencephalic colliculi in the rabbit augmented ventilation and sequentially elicited chest wall tremors and tetany. Investigations conducted during the past several decades would demonstrate stimulation of distributed zones within the midbrain reticular formation elicits starkly disparate effects upon respiratory phase switching. Schmid, Böhmer, and Fallert demonstrated electrical stimulation of the nucleus rubre and emanating axon bundles alternately elicits or inhibits the activity of medullary expiratory-or inspiratory-related units and phrenic nerve discharge with differential latency. A series of studies would later indicate the red nucleus mediates hypoxic ventilatory depression. Periaqueductal gray matter neurons exhibit extensive interconnectivity with suprabulbar, brainstem, and spinal cord zones aptly positioning these units to modulate breathing, autonomic outflow, nociception locomotion, micturition, and sexual behavior. Experimental stimulatory activation of the tectal colliculi and periaqueductal gray matter via electrical current