The high-flow nasal cannula (HFNC) has been recently used in several clinical settings for oxygenation in adults. In particular, the advantages of HFNC compared with low-flow oxygen systems or non-invasive ventilation include enhanced comfort, increased humidification of secretions to facilitate expectoration, washout of nasopharyngeal dead space to improve the efficiency of ventilation, provision of a small positive end-inspiratory pressure effect, and fixed and rapid delivery of an accurate fraction of inspired oxygen (FiO2) by minimizing the entrainment of room air. HFNC has been successfully used in critically ill patients with several conditions, such as hypoxemic respiratory failure, hypercapneic respiratory failure (exacerbation of chronic obstructive lung disease), post-extubation respiratory failure, pre-intubation oxygenation, and others. However, the indications are not absolute, and much of the proven benefit remains subjective and physiologic. This review discusses the practical application and clinical uses of HFNC in adults, including its unique respiratory physiologic effects, device settings, and clinical indications.