Nicotine exposure diminishes the protective breathing and arousal responses to stress (hypoxia). By exacerbating sleep-disordered breathing, this disturbance could underpin the well established association between smoking and the increased risk of sudden infant death syndrome. We show here that the protective responses to stress during sleep are partially regulated by particular nicotinic acetylcholine receptors (nAChRs). We compared responses of sleeping wild-type and mutant mice lacking the beta2 subunit of the nAChR to episodic hypoxia. Arousal from sleep was diminished, and breathing drives accentuated in mutant mice indicating that these protective responses are partially regulated by beta2-containing nAChRs. Brief exposure to nicotine significantly reduced breathing drives in sleeping wild-type mice, but had no effect in mutants. We propose that nicotine impairs breathing (and possibly arousal) responses to stress by disrupting functions normally regulated by beta2-containing, high-affinity nAChRs.