Alterations in microcirculatory permeability are a characteristic of early tissue injury. Moreover, tissue edema is an early indicator of tissue dysfunction, prior to organ failure, because tissue edema is associated with impaired gas exchange, arterial hypoxemia, and may also impair tissue oxygen distribution. As a result of increased microvascular permeability, plasma fluid is lost into the interstitial space, leading to hypovolemia. Currently, no effective pharmacological therapy is available to reduce increased permeability. High mortality rate in sepsis is still mainly associated with endothelial damage. In this regard platelets, besides leukocytes, play a major role for the development of microvascular hyperpermeability. This review considers endothelial cell dysfunction during endotoxemia including current insights into sepsis pathophysiology. New aspects of this complex pathogenesis are illustrated and their relevance for clinical sepsis therapy is emphasized.