Health-care professionals (HCPs) can provide protocol-based care that has a measurable impact on critically ill patients beyond their liberation from mechanical ventilation (MV). Randomized controlled trials have demonstrated that protocols for liberating patients from MV driven by nonphysician HCPs can reduce the duration of MV. The structure and features of protocols should be adapted from published protocols to incorporate patient-specific needs, clinician preferences, and institutional resources. As a general approach, shortly after patients demonstrate that their condition has been stabilized on the ventilator, a spontaneous breathing trial (SBT) is safe to perform and is indicated. Ventilator management strategies for patients who fail a trial of spontaneous breathing include the following: (1) consideration of all remediable factors (such as electrolyte derangements, bronchospasm, malnutrition, patient positioning, and excess secretions) to enhance the prospects of successful liberation from MV; (2) use of a comfortable, safe, and well-monitored mode of MV (such as pressure support ventilation); and (3) repeating a trial of spontaneous breathing on the following day. For patients who pass the SBT, the decision to extubate must be guided by clinical judgment and objective data to minimize the risk of unnecessary reintubations and self-extubations. Protocols should not represent rigid rules but, rather, guides to patient care. Moreover, the protocols may evolve over time as clinical and institutional experience with them increases. Useful protocols aim to safely and efficiently liberate patients from MV, reducing unnecessary or harmful variations in approach.