The interface is the defining element of non-invasive ventilation (NIV). Nowadays different types of interfaces, which differ in terms of shape, mechanical properties and comfort, are available, and their choice and fitting is a key element of NIV success. In the last decade, larger masks covering the entire face and specifically designed helmets have been developed for delivering NIV, theoretically improving comfort and patient tolerance. Recent studies have shown that, despite marked heterogeneity in mask internal volume and compliance, the dynamic dead space and, above all, the clinical efficacy of different masks is on average very similar. Thus, with the exception of the nasal mask and the mouthpiece, a variety of interfaces for NIV can be used in the acute care setting. However, prevention and monitoring of interfaces related side-effects and evaluation of patient tolerance are crucial to avoid NIV failure. To optimize effectiveness and costs, an interface strategy for NIV in acute respiratory failure could be convenient in clinical practice.