Recent studies have identified key pathways involved in the development of pulmonary hypertension. In particular, heterozygous germline mutations in receptors of the transforming growth factor-β superfamily have been shown to underlie some cases of idiopathic pulmonary arterial hypertension. Thus mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for approximately 65% of cases of familial PAH, and 10-20% of sporadic cases. Mutations have been described in almost every exon of the BMPR-II coding sequence. 70% of these are predicted to cause premature truncation of the protein, with some mutations predicted to result in nonsense mediated mRNA decay and complete absence of protein product. Approximately 30% of mutations are missense mutations, resulting in a change in a highly conserved amino acid. Some of these cause disruption of the ligand binding or kinase domain of the receptor, while others lead to failure of receptor trafficking to the cell surface. Evidence is now emerging that dysfunction of these pathways may play an important role in patients in whom no mutation has been identified. Pulmonary artery smooth muscle cells isolated from patients with idiopathic PAH demonstrate abnormal growth reponses to BMPs and TGF-β, whether or not a mutataion can be identified in BMPR-II. Severe PAH can also occur in families with hereditary haemorrhagic telangiectasia, usually associated with mutations in the ALK-1 TGF-β receptor. BMPR-II and ALK-1 signal via the same restricted set of Smad proteins in endothelial cells. The molecular mechanism of the vascular occlusion seen in PAH may involve an imbalance between critical downstream mediators of TGF-β/BMP signalling, the Smad proteins, and upregulation of mitogen activated protein kinase pathways. The level of expression of the BMPR-II receptor and the phosphorylated isoforms of downstream Smads is reduced in the lung tissue of PAH patients whether or not a muation is detected in the coding region of the gene. Studies of the BMPR-II promoter reveal powerful negative regulators of gene expression, which seem to be regulated by inflammatory stimuli. It is likely that other genetic or environmental stimuli are required for the clinical manifestation of PAH in patients carrying BMPR-II mutations, since it is estimated that only 15-20% of disease gene carriers eventually develop the disease. This ‘second hit’ may involve further inherited or somatic mutations in related pathways, or exposure to other agents known to be associated with PAH, such as appetite suppressant drugs many of which influence the metabolism of serotonin. Recent genetic association studies have shown an increased frequency of polymorphisms regulating the expression of the serotonin transporter in PAH and in hypoxic pulmonary hypertension. This polymorphism effects the level of expresion of the transporter. Interestingly, we have shown that serotonin portentiates the development of pulmonary hypertension in a mouse deficient in BMPR-II, providing a potential link between these two systems.