Because of the lack of adequate animal models, much of our knowledge of the pathogenesis of primary pulmonary hypertension has come from clinical experiences. The clinical response to vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the pathologic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunction, as a primary abnormality in primary pulmonary hypertension, provides an explanation for the pathologic and clinical expression of the disease in its various forms. Other clinical features of the disease, such as age of onset and rapidity of progression, may be influenced by triggers of the disease process and underlying individual genetic susceptibility. As we have been able to correlate the spectrum of clinical observations with advances in vascular biology, newer, more focused and effective therapies should begin to emerge.