Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology characterized by sustained elevations in pulmonary artery pressure. Familial PPH accounts for approximately 6% of cases of PPH and has an autosomal-dominant mode of inheritance. Studies over the last 15 years have identified that both familial and sporadic cases of PPH have an association with mutations in the bone morphogenic protein receptor (BMPR) type II gene. Prostacyclin (PGI2) is currently the standard of care for most patients with severe PPH. Prostacyclin synthase (PGIS) catalyzes the production of PGI2 from prostaglandin H2 and is a critical regulatory step in PGI2 production. Decreased or absent expression of PGIS in the pulmonary microvasculature has been reported in patients with PPH, raising the potential for PGIS as a disease modifying gene. We hypothesize that functional mutations in the PGIS promoter affect transcription regulation of PGI2 production and play a pivotal role in PPH pathogenesis.