This chapter on respiratory failure and mechanical ventilation provides essential information about how to support children with severe respiratory disorders. The authors discuss multiple modes of respiratory support, including high-flow nasal cannula oxygen, noninvasive ventilation with continuous positive airway pressure and bilevel positive airway pressure, as well as conventional, high-frequency, and alternative modes of invasive ventilation. The section on invasive mechanical ventilation includes key information regarding gas exchange goals, modes of ventilation, patient–ventilator interactions, ventilator parameters (including tidal volume, end-expiratory pressure, and peak plateau pressure), extubation readiness testing, and troubleshooting. The authors also provide the new consensus definition of pediatric acute respiratory distress syndrome. Also included are multiple figures and indispensable information on adjunctive therapies (inhaled nitric oxide, surfactant, prone positioning, and corticosteroids) and respiratory monitoring (including capnography and airway graphics analysis).