Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy, the respiratory muscles may be rendered almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury seems to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where meaningful controlled trials can be done, and thus, it is not possible to give concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow.