In 2013 new “mouthpiece ventilation” modes are being introduced to commercially available portable ventilators. Despite this, there is little knowledge of how to use noninvasive intermittent positive pressure ventilation (NIV) as opposed to bi-level positive airway pressure (PAP) and both have almost exclusively been reported to have been used via nasal or oro-nasal interfaces rather than via a simple mouthpiece. Non-invasive ventilation is often reported as failing because of airway secretion encumbrance, because of hypercapnia due to inadequate bi-level PAP settings, or poor interface tolerance. The latter can be caused by factors such as excessive pressure on the face from poor fit, excessive oral air leak, anxiety, claustrophobia, and patient-ventilator dys-synchrony. Thus, the interface plays a crucial role in tolerance and effectiveness. Interfaces that cover the nose and/or nose and mouth (oro-nasal) are the most commonly used but are more likely to cause skin breakdown and claustrophobia. Most associated drawbacks can be avoided by using mouthpiece NIV. Open-circuit mouthpiece NIV is being used by large populations in some centers for daytime ventilatory support and complements nocturnal NIV via “mask” interfaces for nocturnal ventilatory support. Mouthpiece NIV is also being used for sleep with the mouthpiece fixed in place by a lip-covering flange. Small 15 and 22mm angled mouthpieces and straw-type mouthpieces are the most commonly used. NIV via mouthpiece is being used as an effective alternative to ventilatory support via tracheostomy tube (TMV) and is associated with a reduced risk of pneumonias and other respiratory complications. Its use facilitates “air-stacking” to improve cough, speech, and pulmonary compliance, all of which better maintain quality of life for patients with neuromuscular diseases (NMDs) than the invasive alternatives. Considering these benefits and the new availability of mouthpiece ventilator modes, wider knowledge of this technique is now warranted. This review highlights the indications, techniques, advantages and disadvantages of mouthpiece NIV.