Hemodynamic instability of the preterm infant has challenged neonatologists since the inception of the field. The inherent abnormal condition and dynamic physiology of the preterm infant make it difficult to define and subsequently treat neonatal hypotension. Since neonatal hypotension contributes to the several complications of prematurity, significant research efforts have been carried out to learn how to define and treat it. We review the obstacles encountered in defining and treating neonatal hypotension and apply this knowledge to the special consideration of preterm infants with necrotizing enterocolitis.