Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin and nitric oxide pathways have significantly improved outcomes. However, for the vast majority of patients, PAH remains a life limiting illness with no prospect of cure. PAH is characterized by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH.