Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a relentless course toward heart failure and early death. Existing PAH therapies, all of which were developed originally to treat systemic vascular diseases, cannot reverse the disease or markedly improve survival and are expensive. Although there has been a recent increase in the number of potential new therapies emerging from animal studies, less than 3% of the active PAH clinical trials are examining such therapies. There are many potential explanations for the translational gap in this complex multifactorial disease. We discuss these challenges and propose solutions that range from including clinical endpoints in animal studies and improving the rigor of human trials to conducting mechanistic early-phase trials and randomized trials with innovative designs based on personalized medicine principles. Global, independent patient and tissue registries and enhanced communication among academics, industry, and regulatory authorities are needed. The diversity of the mechanisms and pathology of PAH calls for broad comprehensive theories that encompass emerging evidence for contributions of metabolism and inflammation to PAH to support more effective therapeutic target identification.