Angiopoietin-1 (ANG-1) is a secreted ligand for Tie-2, a tyrosine-kinase receptor expressed primarily on vascular endothelial cells and early hematopoietic cells. ANG-1/Tie-2 signaling promotes angiogenesis during the development, remodeling, and repair of the vascular system. Transgenic mice lacking expression of either ANG-1 or Tie-2 fail to develop a fully functional cardiovascular system and die before birth. Postnatally, the angiogenic activity of ANG-1/Tie-2 is required during normal tissue repair and remodeling of the female endometrium in the menstrual cycle. ANG-1/Tie-2 signaling appears to be regulated by Angiopoietin-2 (ANG-2), a natural antagonist for Tie-2 that exerts its effects through an internal autocrine loop mechanism. In addition to suppressing endothelial cell activation by inhibiting the expression of adhesion and inflammatory molecules, Ang-1 enhances endothelial cell survival and capillary morphogenesis, and lessens capillary permeability. As such, ANG-1 has potential to become an effective therapeutic agent for treating various endothelium disorders, including several severe human pulmonary diseases. The efficacy of cell-based Ang-1 gene therapy for acute lung injury (ALI) has recently been studied in a rat model of ALI. The results of this study show that such therapy can markedly improve lung condition and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress injury (ARDI), a significant cause of morbidity and mortality in critically ill patients.