Respiratory muscle-associated stretch has been implicated in normal lung development (fetal breathing movements) and post-pneumonectomy lung growth. To test the hypothesis that mechanical stretch from diaphragmatic contraction contributes to lung growth, we performed left phrenic nerve transections (PNT) in mice with and without ipsilateral pneumonectomy. PNT was demonstrated by asymmetric costal margin excursion and confirmed at autopsy. In mice with two lungs, PNT was associated with a decrease in ipsilateral lung volume (p<.05) and lung weight (p<.05). After pneumonectomy, PNT was not associated with a change in activity level, measureable hypoxemia or altered minute ventilation; however, microCT scanning demonstrated altered displacement and underinflation of the cardiac lobe within the first week after pneumonectomy. Coincident with the altered structural realignment, lung impedance measurements, fitted to the constant phase model, demonstrated elevated airway resistance (p<.05), but normal peripheral tissue resistance (p>.05). Most important, PNT appeared to abrogate compensatory lung growth after pneumonectomy; the weight of the lobes of the right lung were significantly less than pneumonectomy alone (p<.001) and indistinguishable from non-surgical controls (p>.05). We conclude that the cyclic stretch associated with diaphragmatic muscle contraction is a controlling factor in post-pneumonectomy compensatory lung growth.