The diaphragm is the thin dome-shaped muscle that separates the thoracic cavity from the abdominal contents. Functionally, the diaphragm is the principal inspiratory muscle in humans and other mammals, and importantly, a healthy diaphragm is essential to achieve adequate pulmonary ventilation and gas exchange across the blood/gas interface. In addition to pulmonary gas exchange, the diaphragm also contributes to important non-breathing functions such coughing and sneezing. Compared to locomotor muscles, the diaphragm is anatomically unique and is the only skeletal muscle that is chronically active. This chapter provides a summary of diaphragm structure and function and examines the plasticity of diaphragm muscle fibers in response to both increased and decreased contractile activity. The impact of aging and chronic diseases on diaphragmatic function is also considered. The chapter concludes with a detailed discussion of the important clinical problem of ventilator-induced diaphragm dysfunction.