The complexity of postnatal cardiovascular transition has only recently been better appreciated in the very low birth weight neonate. As blood pressure in itself poorly represents systemic blood flow, especially when the fetal channels are open and the developmentally regulated vital organ assignment may not have been completed, efforts to measure systemic blood flow have resulted in a novel, yet incomplete, understanding of the principles and clinical relevance of cardiovascular adaptation during postnatal transition in this patient population. This article describes the definition of hypotension based on the principles of cardiovascular physiology, and reviews the tools available to the clinician and researcher at the bedside to examine the complex relationship among blood pressure, systemic and organ blood flow, and tissue oxygen delivery and oxygen demand in vital and non-vital organs in the very low birth weight neonate. Only after gaining an insight into these complex relationships and processes will we be able to design clinical trials of selected treatment modalities targeting relevant patient sub-populations for the management of neonatal cardiovascular compromise. Only clinical trials based on a solid understanding of developmental cardiovascular physiology tailored to the appropriate patient sub-population hold the promise of being effective and practical, and can lead to improvements in both hemodynamic parameters and clinically relevant outcome measures.