A fundamental understanding of the developmental biology of the pulmonary vascular bed is important to unravel the complexities of persistent pulmonary hypertension of the newborn, and of pulmonary hypertension secondary to congenital heart defects. The new focus is on the cellular and biology of the vessel wall. Abnormalities in endothelial smooth muscle interactions, resulting in smooth muscle differentiation, hyperplasia, hypertrophy, and migration into the subendothelium may explain and ultimately cause the control of heightened pulmonary vascular reactivity and should allow us to induce regression of structural changes that preclude corrective cardiac surgery within the neonate. This chapter will discuss what's known about normal and abnormal pulmonary vascular development associated with functional properties of the perinatal circulation. The structural response to specific perturbations are going to be addressed and therefore the discussion are going to be directed to a search of unanswered questions through new avenues in research.