Patients with impending respiratory failure often require mechanical ventilation to optimize gas exchange. Although this form of assisted ventilation is required for survival, its persistent use results in diaphragm weakness and muscle fiber atrophy. There is strong evidence that mechanical ventilation alters the structure and function of the diaphragm, resulting in prolonged dependence on assisted ventilation and long-term consequences such as a delayed functional recovery, reduced quality of life and increased risk of mortality. This review summarizes the mechanisms underlying diaphragm dysfunction due to prolonged mechanical ventilation, highlights the role of inspiratory muscle exercise as a strategy to counter diaphragm weakness, and identifies the parameters of an evidence-supported exercise prescription for difficult to wean patients.