Histological and electron microscopic studies over the last four decades have highlighted plump, enlarged endothelial, smooth muscle and fibroblastic cellular elements with increased endoplasmic reticulum (ER), Golgi stacks and vacuolation in pulmonary arterial lesions in human and in experimental [hypoxia and monocrotaline(MCT)] pulmonary arterial hypertension (PAH). However, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by membrane tethers, SNAREs and SNAPs and to suggest how their dysfunction, directly and/or indirectly, might contribute to development of PAH in experimental models and in man, including that due to mutations in BMPR2.