The diaphragm is the main inspiratory muscle and is required to be highly active throughout the life span. The diaphragm muscle must be able to produce and sustain various behaviors that range from ventilatory to nonventilatory such as those required for airway maintenance and clearance. Throughout the life span various circumstances and conditions may affect the ability of the diaphragm muscle to generate requisite forces, and in turn the diaphragm muscle may undergo significant weakness and dysfunction. For example, hypoxic stress, critical illness, cancer cachexia, chronic obstructive pulmonary disorder, and age-related sarcopenia all represent conditions in which significant diaphragm muscle dysfunction exits. This perspective review article presents several interesting topics involving diaphragm plasticity in aging and disease that were presented at the International Union of Physiological Sciences Conference in 2017. This review seeks to maximize the broad and collective research impact on diaphragm muscle dysfunction in the search for transformative treatment approaches to improve the diaphragm muscle health during aging and disease.