© 2014 by Nova Science Publishers, Inc. All rights reserved. Acute lung injury (ALI) is a life-threatening syndrome associated with high morbidity and mortality. ALI is characterized by the increased permeability of the alveolar-capillary membrane, edema, uncontrolled neutrophil migration into the lung, and diffuse alveolar damage, leading to acute hypoxemic respiratory failure. ALI can occur in response to a number of insults that cause either direct or indirect injury to the lung. The most common indirect insult leading to ALI is the release of lipopolysaccharide (LPS) from the outer cell wall of Gram-negative (G-) bacteria producing sepsis. Other common causes include severe trauma with shock, multiple transfusions, burn injury, pneumonia and aspiration of gastric contents. During the development of LPS mediated ALI, the endothelium lining the lung micro-vessels becomes injured. The vascular endothelium is a single-cell layer that forms the interface between circulation and the underlying vascular wall. One of the most striking features of pulmonary microvascular endothelial cells is that they possess a highly impermeable barrier. The disruption of endothelial barrier integrity and the subsequent development of pulmonary edema is a major pathological event responsible for the respiratory failure in ALI. The endothelium also has profound effects on vascular tone, growth, and differentiation. Therefore, the following chapter will underline different mechanisms responsible for the disruption of endothelial function. In particular, we will detail the source and the biochemical effects of reactive species in sepsis induced ALI. Finally, this chapter will describe recent advances and current shortcomings in the management of ALI.