Primary pulmonary hypertension (PPH) is a disease characterized clinically by the progressive increase in pulmonary artery impedance, which ultimately produces right ventricular failure and death. At the time most patients with PPH present to clinical attention, pathologic lesions include pulmonary artery medial hypertrophy, adventitial thickening, and neointimal lesions. Neointimal lesions are new vascular structures composed of smooth muscle cells (SMC) and extracellular matrix located on the lumenal side of the inner elastic lamina or, if the vessel is too small to have an inner elastic lamina, between the endothelium and the medial layer of the vessel. The terms “neointima” and “neointimal lesions” are used interchangeably in this review. Nearly all active remodeling (as defined by extracellular matrix gene expression) in patients with severe pulmonary hypertension occurs in the neointima (1‐5). This observation underscores the importance of understanding how pulmonary vascular neointimal lesions develop but the pathogenesis and natural history of neointimal lesion formation in PPH are poorly understood. On the basis of animal studies, and by analogy to systemic arterial disease, it seems likely that endothelial injury is required (6). Whether injury occurs secondary to infection (7), ingestion of toxins (8), or activation of autoimmunity (9) remains speculative. Although vascular injury appears necessary to initiate remodeling, other factors besides injury are likely required before pulmonary vascular neointimal lesions develop since the pulmonary artery histology in traditional animal models, in which remodeling is initiated by monocrotaline or hypoxic injury, does not develop lesions that resemble the neointimal lesions of PPH. Hemodynamic forces and injury-induced biochemical mediators are important components in mechanisms of systemic vascular remodeling, including atherosclerosis, restenosis after angioplasty, and neointimal lesions following vascular bypass surgery. New studies suggest hemodynamic factors may be as important in the pulmonary vasculature as they are in the systemic vasculature.