Aortic cross-clamping (AoX) and unclamping are associated with severe hemodynamic disturbances in virtually all organs and systems. The main hemodynamic changes induced by AoX result from an increase in impedance to aortic flow, an increase in systemic vascular resistance and afterload, blood volume redistribution caused by collapse and constriction of venous vasculature distal to the aortic clamp, and a subsequent increase in preload. Preload may not increase if the aorta is clamped distal to the celiac artery; in that case, blood volume from distal venous vasculature may be redistributed to the splanchnic vasculature without associated increases in preload. Increases in afterload and preload demand an increase in contractility, which results in an autoregulatory increase in coronary blood flow. Without increases in coronary blood flow and myocardial contractility, decompensation may occur. Aortic cross-clamping is associated with the formation and release of many mediators which constitute a double-edged sword: they may mitigate or aggravate the harmful hemodynamic effects of AoX and unclamping. Injuries to the lungs, kidneys, spinal cord, or abdominal viscera are caused mainly by ischemia and reperfusion of organs distal to aortic cross-clamping. A clear understanding of the pathophysiologic mechanisms involved in these processes should help to promote rational, well-focused, and effective measures to prevent and treat homeostatic disturbances occurring during AoX and unclamping.