Pulmonary arterial hypertension (PAH), a Group 1 pulmonary hypertension (PH), is a disease of progressive pulmonary vascular remodeling and dysfunction for which there is no cure and only minimally effective treatment. Though traditionally discouraged for PAH, emerging evidence suggests exercise as a potential therapeutic. However, current training approaches generally fail to lower elevated pulmonary pressure, or mitigate right ventricular maladaptive hypertrophy, a major determinant of survival in PAH. The clinical and animal studies of the Brown Laboratory have been directed towards defining the physiological and biochemical consequences and functional outcomes following acute and chronic exercise in PH, to permit much needed optimization of exercise prescription for patients. This seminar will discuss studies testing the hypothesis of recent work- that optimal training outcomes for PH require exercise parameters that strongly stimulate the pulmonary vascular endothelium, and maximize favorable cardiac and skeletal muscle adaptations (e.g. metabolic), while reducing risk for exercise cardiac wall stress-induced acceleration of right heart dysfunction. We will present evidence in a Sprague-Dawley rat model suggesting superior benefit of high intensity interval training (HIIT) for the treatment of PAH, but with a caveat that responses to HIIT and other types of exercise in experimental PH are phenotype- and severity- dependent. We will discuss what we may be able to glean about potentially unsafe exercise training approaches from alarming exercise hemodynamics, mortality, and RV maladaptation in PH rats. Data from two novel in-vivo methodologies supporting the study of exercise responses in experimentally-induced PH will also be presented- implantable telemetry recording of pulmonary pressures during treadmill running, and assessment of skeletal muscle blood flow during treadmill running using fluorescent microspheres. Finally, we will look at recent clinical data piloting the use of an unsupervised exercise intervention for patients with PAH and discuss important remaining exercise prescription knowledge gaps gleaned from animal and clinical optimization studies. The experimental protocols for studies presented from the Brown Lab were approved by the Institutional Animal Care and Use Committee of Indiana University, which is in compliance with National Iinstitutes of Health guidelines. All animals received care in compliance with the Guide for the Care and Use of Laboratory Animals 8th edition, Copyright 2011 by the National Academy of Sciences. For animal surgeries, the anaesthetic used was inhaled isofluorane (2.5%). Prior to tissue harvest, rats of these studies were killed under general anaesthesia (inhaled isofluorane (5%)) via exsanguination.