Idiopathic pulmonary arterial hypertension (PAH) is a devastating condition, which untreated leads to death from right heart failure within three years from diagnosis. Although new treatments have been developed over the past few years, there remains a need for therapies which modigy disease progression and reverse the process of pulmonary vascular remodelling. Approximately 10% of cases of PAH are familial. The disease segregates as an autosomal dominant condition with reduced penetrance. In 2000, disease causing heterozygous germline mutations were identified in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II), a receptor member of the transforming growth factor-β. Mutations in the BMPR-II gene have now been identified in more than 70% of families with PAH, as well as 10-26% of sporadic cases of idiopathic PAH. Mutations in BMPR-II may be missense, nonsense or frameshift mutations. About 30% of mutations are missense producing a change in highly conserved amino acids in critical functional regions of the receptor. Such mutations occur in the kinase and ligand binding domain of the receptor, or cause accumulation of the receptor in the endoplasmic reticulum. The latter mutations may be amenable to therapeutic approaches aimed at encouraging receptor trafficking to the cell surface. The majority of mutations lead to truncation of the receptor or allelic loss due to nonsense mediated RNA decay. The wild type BMPR-II receptor exists as a heterodimer at the cell surface forming complexes with type I BMP receptors. On BMP ligand binding, the constitutively active serine-threonine kinase domain of the BMPR-II phosphorylates the type I receptor. The activated type I receptor then phosphorylates downstream signalling intermediaries termed Smad proteins. BMPR-II mutation is associated with reduced activation of Smad proteins in the majority of cases. However, surprisingly, the regulation of many BMP-induced genes are not altered by BMPR-II mutation. This probabaly reflects the presence of alternative Smad-independent pathways of BMP signalling, for example via mitogen activated protein kinases (MAPK). BMPR-II mutation also reduces MAPK signalling in response to BMPs. Our group have identified that BMPR-II mutation in pulmonary artery smooth muscle cells leads to a failure of the antiproliferative and proapoptotic effects of BMPs. This effect may be mediated by dysregulation of BMP-induced transcription factors in the inhibitor of DNA binding (Id) family. BMPs exert diverse and tissue specific effects. In pulmonary artery endothelial cells, BMPs are promote growth and survival, in contrast to their effects in smooth muscle cells. The presence of BMPR-II dysfunction in endothelial cells promotes apoptosis. The combination of increased endothelial apoptosis and enhanced smooth muscle cell survival is likely to contribute to the pathogenesis of PAH. A further important functional consequence of BMPR-II mutation is an altered growth response to TGF-β. Thus smooth muscle cells with dysfunctional BMPR-II are resistant to the growth suppressive effects of TGF-β. We have confirmed that reduced function of BMPR-II and increased TGF-β signalling are both features of widely used rodent models of PAH, triggered by chronic hypoxia or exposure to the plant alkaloid monocrotaline. These observations support the use of anti-TGF-β therapy in PAH. Studies in knockout mice have confirmed that additional stimuli are necessary to promote the development of PAH on a background of BMPR-II deficiency. Thus heterozygous BMPR-II knockout mice only develop more severe pulmonary hypertension than wild type controls when exposed to additional insults. We have shown that increasing circulating serotonin levels is one means by which the pulmonary hypertensive phenotype can be uncovered in the mouse. This fits with the observations in man that disease gene penetrance is usually less than 50% in familial PAH and that additional triggers are necessary for disease manifestation.