BACKGROUND: The goal of mechanical ventilation in acute hypoxemic respiratory failure is to support adequate gas exchange without harming the lungs. How patients are mechanically ventilated can significantly impact their ultimate outcomes. METHODS: This review focuses on emerging evidence regarding strategies for mechanical ventilation in patients with acute hypoxemic respiratory failure including: low tidal volume ventilation in the acute respiratory distress syndrome (ARDS), novel ventilator modes as alternatives to low tidal volume ventilation, adjunctive strategies that may enhance recovery in ARDS, the use of lung-protective strategies in patients without ARDS, rescue therapies in refractory hypoxemia, and an evidence-based approach to weaning from mechanical ventilation. RESULTS: Once a patient is intubated and mechanically ventilated, low tidal volume ventilation remains the best strategy in ARDS. Adjunctive therapies in ARDS include a conservative fluid management strategy, as well as neuromuscular blockade and prone positioning in moderate-to-severe disease. There is also emerging evidence that a lung-protective strategy may benefit non-ARDS patients. For patients with refractory hypoxemia, extracorporeal membrane oxygenation should be considered. Once the patient demonstrates signs of recovery, the best approach to liberation from mechanical ventilation involves daily spontaneous breathing trials and protocolized assessment of readiness for extubation. CONCLUSIONS: Prompt recognition of ARDS and use of lung-protective ventilation, as well as evidence-based adjunctive therapies, remain the cornerstones of caring for patients with acute hypoxemic respiratory failure. In the absence of contraindications, it is reasonable to consider lung-protective ventilation in non-ARDS patients as well, though the evidence supporting this practice is less conclusive. Journal of Hospital Medicine 2014;9:469-475. © 2014 Society of Hospital Medicine.