Persistent low perfusion and low blood pressure are the two major events in the pathogenesis of irreversible shock. This review is focused on our recent study on the mechanism of, and a new therapeutic approach to the two events in IS. One of the main causes of persistent low perfusion are leukocyte adhesion on venule walls and plugging in capillaries which comes from the low wall shear stress or shear rate, and high leukocyte–endothelial adhesion force in IS. However, blockade of leukocyte adhesion by monoclonal antibodies against the adhesion molecules can only attenuate the number of sticking WBC in venules, but cannot make an appreciable improvement in capillary reflow and survival rate in IS, because it is difficult for the agents to flow into an obstructed capillary. We have shown that the administration of Polydatin, a crystalline product isolated from a traditional Chinese medicine, can restore the pulse pressure with high survival rate in irreversible shock. With an increase in pulse pressure, and the highly dispersive force resulting from pulsatile blood flow, the stationary blood cells can be pushed away from the obstructed capillary and thus promote capillary reflow. Therefore, enhancement of pulse pressure is a key factor for the treatment of low perfusion in irreversible shock. Hyperpolarization of arteriolar smooth muscle cells occurs in irreversible shock, which inhibits the potential-operated calcium channel and the influx of Ca²⁺ in arteriolar smooth muscle cells stimulated by norepinephrine, and finally leads to low vascular contractile responsiveness with refractory hypotension in irreversible shock. Activation of the potassium channels K_ATP and BK_Ca is involved in arteriolar smooth muscle cells hyperpolarization. In irreversible shock, ATP depletion, intracellular acidosis, ONOO⁻ formation, and enhancement of a calcium spark results in activation of K_ATP and BK_Ca and consequent arteriolar smooth muscle cell hyperpolarization. Therefore, a new therapeutic strategy for refractory hypotension was suggested, including blockade of potassium channel activation to reconstitute vasoreactivity and the administration of vasopressors to elevate blood pressure in the treatment of irreversible shock.