Experimental evidence suggests that controlled mechanical ventilation (CMV) can induce dysfunction of the diaphragm, resulting in an early-onset and progressive decrease in diaphragmatic force-generating capacity, called ventilator-induced diaphragmatic dysfunction (VIDD). The mechanisms of VIDD are not fully elucidated, but include muscle atrophy (resulting from lysosomal, calpain, caspase and proteasome activation), oxidative stress, structural injury (disrupted myofibrils, increased numbers of lipid vacuoles, and abnormally small and disrupted mitochondria), myofiber remodeling and mitochondrial dysfunction. The major clinical implication of the VIDD is to limit the use of CMV to the extent possible. Partial (assisted) modes of ventilatory support should be used whenever feasible, since these modes attenuate the deleterious effects of mechanical ventilation on respiratory muscles.