Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded protein response (UBR) in the Endoplasmic Reticulum (ER) in normal cells. GRP78 force the unfolded proteins to refold or degrade using cellular degradation mechanisms. Under stress, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes it a tool for pathogens (bacterial, fungal and viral) to enter the cell and to start different pathways leading to pathogenesis. Additionally, GRP78 is overexpressed on the membranes of various cancer cells and increase the aggressiveness of the disease. The current review summarizes structure, function, and different mechanisms GRP78 mediate in response to normal or stress conditions. GRP78 targeting and possible inhibition mechanisms are also covered in the present review aiming to prevent the virulence of pathogens and cancer. Display omitted