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Prolonged ischemia followed by reperfusion (I/R) results in impaired endothelial cell function in all segments of the microvasculature. Moreover, endothelial dysfunction plays a major role in the genesis of the reperfusion component of total tissue injury in I/R. Thus, preservation of endothelial function is an important therapeutic goal for ameliorating injury in tissues subjected to I/R. An accumulating body of evidence indicates that both microvascular endothelium and parenchymal cells can be rendered resistant to the pathological effects of I/R by antecedent exposure to brief periods of ischemia, a phenomenon referred to as ischemic preconditioning (IPC). Although the mechanisms underlying the microvascular effects of preconditioning have been far less extensively studied, work conducted to date indicates that there are fundamental differences in the signaling pathways that underlie the adaptive transformation to a protected or defensive phenotype in the endothelium compared to those that contribute to the development of a preconditioned state in parenchymal cells. Thus, the purposes of this review are to summarize our current understanding of the mechanisms whereby IPC induces the adaptive transformation to a protected or defensive phenotype in parenchymal cells and to compare and contrast this with the signaling pathways that invoke a preconditioned state in arteriolar, capillary, and venular endothelium. In addition, we highlight understudied areas with regard to microvascular protection afforded by antecedent ischemia in the hopes that this will stimulate investigation of the underlying mechanisms. Understanding these signaling pathways may provide a mechanistic rationale for the development of novel treatment interventions that target both the microcirculatory and parenchymal sequelae to I/R, thereby maximizing the therapeutic potential of the protected phenotypes produced by pharmacological preconditioning.