The Centers for Disease Control and Prevention (CDC) released ventilator-associated event (VAE) definitions in 2013. The new definitions were designed to track episodes of sustained respiratory deterioration in mechanically ventilated patients after a period of stability or improvement. More than 2,000 U.S. hospitals have reported their VAE rates to the CDC, but there has been little guidance to date on how to prevent VAEs. Existing ventilator-associated pneumonia prevention bundles are unlikely to be optimal insofar as pneumonia accounts for only a minority of VAEs. This review proposes a framework and potential intervention set to prevent VAEs on the basis of studies of VAE epidemiology, risk factors, and prevention. Work to date suggests that the majority of VAEs are caused by four conditions: pneumonia, fluid overload, atelectasis, and acute respiratory distress syndrome. Interventions that minimize ventilator exposure and target one or more of these conditions may therefore prevent VAEs. Potential strategies include avoiding intubation, minimizing sedation, paired daily spontaneous awakening and breathing trials, early exercise and mobility, low tidal volume ventilation, conservative fluid management, and conservative blood transfusion thresholds. Interventional studies have thus far affirmed that minimized sedation, paired daily spontaneous awakening and breathing trials, and conservative fluid management can reduce VAE rates and improve patient-centered outcomes. Further studies are needed to evaluate the impact of the other proposed interventions, to identify additional modifiable risk factors for VAEs, and to measure whether combining strategies into VAE prevention bundles confers additional benefits over implementing one or more of these interventions in isolation.