This chapter reviews the current status of combining the new evolving technologies of CO2 monitoring and non-invasive positive pressure ventilation (NPPV). It explores the advantages as well as the challenges that prompt further research. The non-invasive character of both NPPV and capnography make the combination attractive for the clinical management of acute and chronic respiratory failure. Several different types of patient interfaces are available for the delivery of non-invasive ventilation, including full face masks, complete face masks, nasal masks, sealed helmets, nasal pillows, mouthpieces and custom-fabricated masks. Sidestream gas measurement offers a number of sampling locations, including: inside the mask, at the mask outlet, or with the nasal cannula at or near the patient's nostrils. It is plausible that the synergies between NPPV and time/volumetric capnography will help the clinician to more rapidly identify therapeutic pressure levels that optimize CO2 elimination and patient work of breathing-key objectives for non-invasive ventilation.