Sleep brings major challenges for the control of ventilation in humans, particularly the regulation of arterial carbon dioxide pressure (P_aCO2). In patients with COPD, chronic hypercapnia is associated with increased mortality. Therefore, nocturnal high-level noninvasive positive-pressure ventilation (NIV) is recommended with the intention to reduceP_aCO2down to normocapnia. However, the long-term physiological consequences ofP_aCO2“correction” on the mechanics of breathing, gas exchange efficiency and resulting symptoms (i.e.dyspnoea) remain poorly understood. Investigating the influence of sleep on the neural drive to breathe and its translation to the mechanical act of breathing is of foremost relevance to create a solid rationale for the use of nocturnal NIV. In this review, we critically discuss the mechanisms by which sleep influences ventilatory neural drive and mechanical consequences in healthy subjects and hypercapnic patients with advanced COPD. We then discuss the available literature on the effects of nocturnal NIV on ventilatory neural drive and respiratory mechanics, highlighting open avenues for further investigation.