The principles of ventilation and perfusion distribution in the lung form the foundation of pulmonary physiology and remain cornerstones in caring for critically ill patients. Due to improved imaging technologies with greater spatial resolution, our understanding of the determinants of local ventilation and blood flow have evolved over the past five decades. This review provides a brief history of how the concepts governing regional ventilation and perfusion have developed and presents the most recent studies that are shaping new perspectives on the determinants of ventilation and perfusion. How these new principles apply to acute lung injury and gas exchange in the intensive care unit(ICU) are reviewed.