The cuff of the endotracheal tube (ETT) is designed to provide a seal within the airway, allowing airflow through the ETT but preventing passage of air or fluids around the ETT. Deliberate or inadvertent movement of the ETT may affect cuff pressure or shift folds in the cuff, mobilizing pooled secretions. When this seal is compromised, microaspirations contaminated with gastric contents or bacterially colonized oral secretions can occur that leave the patient susceptible to a host of problems, such as hypoxia, pneumonitis, and respiratory infections. These complications are costly in terms of morbidity and mortality, as well as hospital expense. We will discuss the role of the ETT cuff in microaspiration and identify potential directions for future research to improve outcomes in mechanically ventilated patients.