Delivery of genes to the pulmonary vascular endothelium is a rational approach for the investigation and potential therapy of pulmonary vascular diseases. Furthermore, in view of the exposure of this vascular bed to the entire cardiac output, this technique could be used as an efficient basis to achieve systemic delivery of secreted factors. The attraction of direct gene delivery to endothelium for the therapy of vascular disease has been especially heightened in the last couple of years in view of the new discoveries concerning the genetic basis of primary pulmonary hypertension (PPH) (1). In brief, mutations in the bone morphogenetic protein receptor type 2 (BMPR2, a member of the transforming growth factor-β [TGF-β] family of receptors) gene have been found in many patients with familial PPH. Subsequent in vitro studies have confirmed an association between BMPR2 mutations and abnormal proliferative responses in pulmonary endothelial and smooth-muscle cells (2). Other TGF-β signaling pathways may also be involved in this process, and the mechanisms involved may also have relevance for the more common cases of pulmonary vascular disease secondarily associated with chronic airways obstruction, connective tissue diseases, and perhaps HIV infection. Additionally, new evidence is emerging concerning the role of the vasculature in the pathogenesis of emphysema. Vascular endothelial growth factor (VEGF) and its receptors appear to be key for the maintenance of normal alveolar architecture: VEGF receptor inhibition causes emphysema in rats, and both VEGF and its receptor levels are reduced in the lungs of patients with emphysema (3,4).