Lung capillary pressure in healthy humans at rest ranges between 6 and 10 mmHg. At maximal effort or in pathophysiological conditions such as left sided heart disease or massive pulmonary vasoconstriction, for example in high-altitude pulmonary disease, capillary pressure may be markedly elevated. Increased capillary pressure directly affects transendothelial fluid dynamics and thus results in the formation of hydrostatic lung edema. Excessive pressure increases may cause capillary stress failure. Recent studies, however, suggest that the microvascular response to lung capillary hypertension is more complex. Pressure, strain and shear stress cause dysfunction of the capillary endothelium characterized by an imbalanced release of vasoactive mediators. Endothelial dysfunction evokes a multicellular response with features of vasoconstriction, inflammation, and vascular leakage, thrombosis, and remodeling. These active cellular reactions contribute to the pathophysiological process and may be specifically targeted by new therapeutic strategies.