Impaired blood flow in shock and ischemia results in significant organ dysfunction and failure of critical cellular functions. Although some cellular function can proceed via anaerobic mechanisms, a point is reached at which restoration of blood flow and oxygen delivery does not result in restoration of function ("refractory shock" or the "no-reflow phenomenon"). But even if blood flow is restored after shock or ischemia, a second mechanism of cellular injury is initiated: monocytes and neutrophils are activated, resulting in an inflammatory response. Current evidence suggests that the activation of inflammatory cells is triggered by substances from ischemic or injured vascular endothelium that cause leukocyte adherence, activation, and further injury. This review summarizes the current literature on endothelial cell, monocyte, and neutrophil interactions in reperfusion injury after shock or ischemia and suggests how a recently described peptide from the vascular endothelium may play an important role in the cascade.