We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure (PET(CO2)) was gradually reduced during non-rapid eye movement sleep by increasing tidal volume with pressure support mechanical ventilation, causing a reduction in diaphragm electromyogram amplitude until apnea/periodic breathing occurred. We used the reduction in PET(CO2) below spontaneous breathing required to produce apnea (DeltaPET(CO2)) as an index of the susceptibility to apnea. DeltaPET(CO2) was -5 mm Hg in control animals and changed in proportion to background ventilatory drive, increasing with metabolic acidosis (-6.7 mm Hg) and nonhypoxic peripheral chemoreceptor stimulation (almitrine; -5.9 mm Hg) and decreasing with metabolic alkalosis (-3.7 mm Hg). Hypoxia was the exception; DeltaPET(CO2) narrowed (-4.1 mm Hg) despite the accompanying hyperventilation. Thus, hyperventilation and hypocapnia, per se, widened the DeltaPET(CO2) thereby protecting against apnea and hypopnea, whereas reduced ventilatory drive and hypoventilation narrowed the DeltaPET(CO2) and increased the susceptibility to apnea. Hypoxia sensitized the ventilatory responsiveness to CO2 below eupnea and narrowed the DeltaPET(CO2); this effect of hypoxia was not attributable to an imbalance between peripheral and central chemoreceptor stimulation, per se. We conclude that the DeltaPET(CO2) and the ventilatory sensitivity to CO2 between eupnea and the apneic threshold are changeable in the face of variations in the magnitude, direction, and/or type of ventilatory stimulus, thereby altering the susceptibility for apnea, hypopnea, and periodic breathing in sleep.