Computer models represent a distillation and formalization of our working hypotheses regarding cardiopulmonary structure-function-regulation relationships. This in silico approach facilitates a rigorous cycle of hypothesis testing (quantitative comparison of model predictions to experimental observations), hypothesis refinement (redesign and reformulation of models in light of mis-matches between predictions and data), and model-guided experimental design. We are currently using in silico approaches to study the mechanobiological mechanisms of transition from isolated post-capillary pulmonary hypertension to combined pre/post capillary pulmonary hypertension and the multi-scale mechanisms of right ventricular failure.