Transmigration of neutrophils through vascular endothelial walls into the inflamed tissues is a critical defense mechanism of innate immune system against infection and injury caused by sepsis, trauma, ischemia-reperfusion, and other acute or chronic inflammatory diseases. However, their excessive infiltration and uncontrolled activation may lead to the destruction of normal tissue architecture and unrestrained inflammation. Transendothelial migration (TEM) in a luminal-to-abluminal direction is widely known as the final step of neutrophil migration cascade into the inflamed tissues. Recent studies have shown that neutrophils not necessarily move from the vascular lumen to the extravascular tissues in a one way direction; they also proceed in an opposite direction, known as reverse transendothelial migration (rTEM) to get back into the vascular lumen again. This novel paradigm of neutrophil round trip is currently on the spotlight due to its possible interaction with immune system. Current review highlighting the growing demand of this newly identified neutrophil migratory event will not only rewrite the disease pathophysiology, but also help scientists design novel therapeutic strategy leading to the remission of inflammatory diseases in which controlling exaggerated neutrophil infiltration is a major challenge.