Clinical and pathologic features of primary pulmonary hypertension have been well characterized, but little is known regarding the underlying cause and pathogenesis. The disorder is usually discovered in its late stage, when pulmonary vascular resistance is already severely compromised and the pathologic changes already well developed. It is not surprising, then, that most attempts at defining effective pharmacologic interventions have been disappointing. Some new approaches are clearly needed. The past decade has witnessed the rapid growth of molecular techniques in areas applied to the study of the blood vessel wall, blood coagulation, and the platelet-endothelial cell interaction. Platelet-derived growth factors and other macrophage-derived factors may play important roles in the pathogenesis of the early proliferative lesions found in the small pulmonary arterioles. Other vascular-derived mediators may be important determinants in modulating the vasoconstrictor or vasodilator response in small vessels. A recent brief but pertinent review has highlighted some of the new directions being taken. It appears that the right questions are finally being asked, and we now may have the tools to answer them.