In healthy humans ventilatory chemoreception results in exquisite regulation of arterial blood gases during NREM sleep, but during wakefulness other behavioral and arousal-related influences on breathing compete with chemoreceptive respiratory control. This paper examines the extent of chemoreceptive control of breathing within the normal physiological range in awake and sleeping humans and explores the consequences upon breathing of absent chemoreceptive function. Recent studies of subjects with congenital central hypoventilation syndrome (CCHS) demonstrate the extent of behavioral and arousal-related influences on breathing in the absence of arterial blood gas homeostasis. CCHS subjects lack chemoreceptor control of breathing and seriously hypoventilate during NREM sleep, requiring mechanical ventilation. Many CCHS subjects breathe adequately during many waking behaviors associated with arousal, cognitive activity or exercise--presumably reflecting input to the brainstem respiratory complex from the reticular activating system, the forebrain or mechanoreceptor afferents. In most situations, and despite changes in metabolism, the non-chemoreceptive inputs to breathing result in surprisingly well controlled arterial blood gases in CCHS patients.