The diaphragm is the most important muscle of ventilation. Its contraction is key to the development of intrathoracic pressures. Diseases that affect diaphragmatic function result in decreased pressure-generating capacity by the respiratory muscles. If the involvement is severe or if there is underlying respiratory pathology, diaphragmatic paralysis can lead to overt ventilatory failure. Diaphragmatic involvement can occur unilaterally or bilaterally from systemic diseases or from diseases primarily affecting the diaphragm. Whatever the cause, unilateral diaphragmatic paralysis is usually well tolerated if there is no underlying lung or ribcage pathology. However, under conditions of increased loads, unilateral diaphragmatic paralysis can cause dyspnea and hypoxemia and require treatment. Bilateral diaphragmatic paralysis of any etiology is usually symptomatic and may result in ventilatory failure when severe, or when associated with underlying lung pathology. In some patients unilateral or bilateral paralysis can improve spontaneously but usually over prolonged periods of time. In patients with significant symptoms or development of ventilatory failure, symptoms and outcomes are improved by treatment with noninvasive ventilation or, in selected cases of unilateral paralysis, surgical plication of the diaphragm.