There is incredible potential to advance our understanding of disease pathogenesis, enhance our diagnostic capability, and revolutionize our treatment modalities with the advent of advanced systems approaches to genetic, genomic, and epigenetic discoveries. Investigation using these technologies is beginning to impact our understanding of pulmonary arterial hypertension (PAH). The following review details work to date on single gene mutations in PAH, and expression array analysis in the disease. The wider use of DNA-based arrays for genome wide association studies (GWAS) and copy number alterations is examined. The impact of epigenomic modulation in the pathobiology of PAH and its therapeutic implications is investigated. Finally, a summary of the capabilities and promises for next-generation sequencing is discussed. A framework for studies of the future is proposed.