The epicardium plays an essential role in coronary artery formation and myocardial development, but signals controlling the development and differentiation of this tissue are not well understood. To investigate the role of platelet-derived growth factor receptor (PDGFR) in development of epicardial-derived vascular smooth muscle cells (VSMCs), we examined PDGFR^-/- and PDGFR epicardial mutant hearts. We found that PDGFR^-/- hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMCs (cVSMCs). This constellation of defects was consistent with a primary defect in the epicardium. To verify that these defects were specific to epicardial derivatives, we generated mice with an epicardial deletion of PDGFR that resulted in reduced cVSMCs distal to the aorta. The regional absence of cVSMCs suggested that cVSMCs could arise from 2 sources, epicardial and nonepicardial, and that both were dependent on PDGFR. In the absence of PDGFR signaling, epicardial cells adopted an irregular actin cytoskeleton, leading to aberrant migration of epicardial cells into the myocardium in vivo. In addition, PDGF receptor stimulation promoted epicardial cell migration, and PDGFR-driven phosphoinositide 3'-kinase signaling was critical for this process. Our data demonstrate that PDGFR is required for the formation of 2 distinct cVSMC populations and that loss of PDGFR-PI3K signaling disrupts epicardial cell migration.