Ischemia followed by reperfusion is associated with typical microvascular disturbances characterized by capillary perfusion break-down (no-reflow), accumulation and adhesion of leukocytes to the microvascular endothelium (reflow-paradox) and impairment of endothelial barrier function, indicating the onset of cellular and/or organ dysfunction. Therapeutic approaches aiming at the prevention of microvascular failure elicited by ischemia/reperfusion, have to be devided into measures interfering with 1) the insult induced during the ischemic period and its consequences from cellular energy depletion and 2) the microvascular disturbances induced during the reperfusion/reoxygenation period. Using various microcirculation models in hamster and/or mouse allowing for chronic visualization of the microcirculation in striated muscle and skin, different therapeutic strategies have been investigated in our laboratory to protect the tissue from the manifestation of postischemic microvascular disturbances. The results are discussed with respect to the potential mode of action of the various therapeutic strategies performed.