Background: The regulation of epithelial cell shape and orientation during lung branching morphogenesis is not clearly understood. Nonmuscle myosins regulate cell size, morphology, and planar cell polarity. Here, we test the hypothesis that nonmuscle myosin II (NM II) regulates lung epithelial morphology in a spatially restricted manner. Results: Epithelial cell orientation at airway tips in fetal mouse lungs underwent a significant transformation at embryonic day (E) E17. Treatment of E15 lung explants with the NM II inhibitor blebbistatin increased airway branching, epithelial cell size, and the degree of anisotropy in epithelial cells lining the airway stalks. In cultured MLE-12 lung epithelial cells, blebbistatin increased cell velocity, but left the migratory response to FGF-10 unchanged. Conclusions: In the developing lung, NM II acts to constrain cell morphology and orientation, but may be suppressed at sites of branching and cell migration. The regulation of epithelial orientation may therefore undergo dynamic variations from E15 to E17. Developmental Dynamics, 2012. © 2012 Wiley Periodicals, Inc.