The main respiratory muscles are under both voluntary and involuntary (automatic) control. These two control systems come from separate sites in the CNS and have separate descending pathways; the final integration of these outputs occurs at segmental levels in the cord. Voluntary control arises from the motor and premotor cortex and descends in the cord in the corticospinal tract. Involuntary control is mediated by both rhythmic and nonrhythmic systems located in the brainstem. Recent studies have associated the classic respiratory centers with specific nuclei in the brainstem. The pneumotaxic center is located in the nucleus parabrachialis, and the medullary respiratory centers are located in the vicinity of the nucleus of the solitary tract (dorsal respiratory group) and the nuclei ambiguus and retroambigualis (ventral respiratory group). Most axons from the medullary nuclei cross in the medulla and descend in the ventral and lateral columns to segmental levels. The classic medullary respiratory centers described by Pitts have been shown to be the site of origin of tonically firing long reticulospinal axons that descend in the ventral and lateral columns. This system is thought to provide a nonrhythmic involuntary biasing of the membrane potential of respiratory motoneurons in the cord. The site of generation of eupnic breathing and the mechanism of rhythm generation remain unknown. However, recent studies indicate that reciprocal inhibition between populations of inspiratory and expiratory cells (bistable oscillator model) does not occur in the medulla; rather we suggest that inhibitory phasing of inspiratory cells generates inspiratory rhythm, and periodic inhibition of tonically active expiratory neurons results in respiratory rhythm. We suggest that the inhibitory phasing occurs in the dorsal respiratory group, which is also the site of integration of respiratory afferents. The main site of integration of the voluntary and involuntary control systems is the cord where the respiratory motoneuron output is determined by descending information from these systems, as well as with intrasegmental and intersegmental reflexes. Separation of the voluntary and involuntary control systems also occurs in man and discrete lesions may interrupt one system without significant alteration of the other.