ABSTRACT: Regular exercise is recommended as part of cystic fibrosis (CF) physiotherapy. Exercise delays the development of pulmonary disease in CF patients; however, the cellular mechanisms responsible for these improvements are unclear. This review expands on the hypothesis that exercise improves CF pathophysiological ion dysregulation via purinergic and adrenergic pathways by describing the effects of 5′ adenosine monophosphate–activated protein kinase (AMPK), atrial natriuretic peptide (ANP), and arginine-vasopressin (AVP) on CF airway epithelia. Activation of AMPK decreases Na+ absorption, increases airway surface liquid, and reduces oxidative stress and inflammation. Plasma ANP inhibits the basolateral Na+/K+-ATPase and may therefore reduce epithelial water absorption. Airway epithelia respond to plasma AVP and secrete AVP in response to elevated bradykinin. AVP stimulates the basolateral Na+/K+/2Cl− exchanger, thereby increasing Cl− secretion, reducing Na+ absorption, and promoting basolateral to luminal water flux. In addition, AVP may increase cilia beat frequency in airway epithelia via a Ca2+-dependent mechanism. This review will describe the effects of exercise on AMPK activation, ANP release, and AVP secretion; we hypothesize that the mechanical and metabolic perturbations that occur with exercise may be beneficial in preventing CF lung pathogenesis by improving airway hydration, mucociliary clearance, and reducing markers of inflammation.