Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response (HCVR), particularly during sleep. We now extend our previous findings to determine whether (1) leptin deficiency affects the hypoxic ventilatory response (HVR), and (2) blockade of the downstream excitatory actions of leptin on melanocortin 4 (MC4) receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same HVR as weight-matched wildtype obese mice. There were no differences in the hypoxic sensitivity between agouti yellow (A^y)mice and weight-matched controls, or neuropeptide Y deficient mice and wildtype littermates. A^y mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity in comparison with weight-matched wildtype controls during NREM sleep (5.8 ± 0.7 vs. 8.9 ± 0.7 ml/min/%CO₂, p < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the HCVR in comparison with wildtype littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness, but that MC4 blockade is associated with depressed hypercapnic sensitivity in NREM sleep.