Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature characterized by elevated pulmonary artery pressure. Currently, there is no cure for this disease, and treatment is palliative. PAH therapies target 3 main pathways: prostacyclin, endothelin, and nitric oxide. The 3 distinct therapeutic pathways targeted have provided the opportunity to explore the efficacy of combination therapy. This article reviews the pharmacokinetic profiles of available therapies and existing clinical trial results that support combination therapy, as well as provides rationale and clinical guidance for combination therapy. Combination therapy may offer an additive and potentially synergistic benefit. The initiation and titration of combination therapy has several pharmacokinetic considerations, such as the onset of drugs' action and time to steady state, as well as potential drug interactions. Although great strides have been made in the treatment of PAH, unanswered questions still remain in regard to combination therapy: (1) Which combination is best? and (2) Is it most appropriate to maximize one drug and then initiate a second drug or to start both drugs simultaneously? Answers to these questions will help identify a safe and effective combination therapy and thus optimize treatment for patients with PAH.