AbstractPlatelet‐derived growth factor receptor alpha (Pdgfrα) identifies cardiac progenitor cells in the posterior part of the second heart field. We aim to elucidate the role of Pdgfrα in this region. Hearts of Pdgfrα‐deficient mouse embryos (E9.5–E14.5) showed cardiac malformations consisting of atrial and sinus venosus myocardium hypoplasia, including venous valves and sinoatrial node. In vivo staining for Nkx2.5 showed increased myocardial expression in Pdgfrα mutants, confirmed by Western blot analysis. Due to hypoplasia of the primary atrial septum, mesenchymal cap, and dorsal mesenchymal protrusion, the atrioventricular septal complex failed to fuse. Impaired epicardial development and severe blebbing coincided with diminished migration of epicardium‐derived cells and myocardial thinning, which could be linked to increased WT1 and altered α4‐integrin expression. Our data provide novel insight for a possible role for Pdgfrα in transduction pathways that lead to repression of Nkx2.5 and WT1 during development of posterior heart field–derived cardiac structures. Developmental Dynamics 239:2307–2317, 2010. © 2010 Wiley‐Liss, Inc.