During pregnancy, trophoblasts invade and transform the maternal spiral arteries that supply blood to the placenta. Recent work has revealed that this process occurs in several stages, and details of the molecular and cellular mechanisms are beginning to emerge, including changes that precede or accompany trophoblastic colonization of the vascular media. Disruption and eventual loss of smooth muscle cells and their associated extracellular matrix are central to physiological transformation. Advances in understanding will lead to the identification of the causative factors involved in failure of remodeling in pathological pregnancies and suggest novel diagnostic and therapeutic avenues.