Rapid sequence intubation (RSI) is a lifesaving technique performed by advanced practice nurses when patients require endotracheal intubation but are at risk for gastric aspiration. In the acute care setting, the procedure often is indicated when critically ill or injured patients exhibit difficulty maintaining a patent airway and/or are displaying inadequate oxygenation and ventilation. The goal of this article is to provide advanced practice nurses with information that promotes safe and effective clinical decision making during RSI on the basis of the current state of the science. Standard RSI practices in stable patients are reviewed, and the need for individualized modifications of this “ideal” practice in unstable, critically ill patients is addressed. Factors predisposing a patient to difficult airway management, proper equipment, and patient preparation are highlighted, along with the relevant pharmacology. Finally, prevention of potential complications during RSI in the acute care setting is discussed.