Background Glucose regulating protein 78 (GRP78) is one member of the Heat Shock Protein family of chaperone proteins (HSPA5) found in eukaryotes. It acts as the master of the Unfolded Protein Response (UPR) process in the lumen of the Endoplasmic Reticulum (ER). Scope Under the stress of unfolded proteins, GRP78 binds to the unfolded proteins to prevent misfolding, while under the load of the unfolded protein, it drives the cell to autophagy or apoptosis. Several attempts reported the overexpression of GRP78 on the cell membrane of cancer cells and cells infected with viruses or fungi. Major conclusions Cell-surface GRP78 is used as a cancer cell target in previous studies. Additionally, GRP78 is used as a drug target to stop the progression of cancer cells by different compounds, including peptides, antibodies, and some natural compounds. Additionally, it can be used as a protein target to reduce the infectivity of different viruses, including the pandemic SARS-CoV-2. Besides, GRP78 targeting is used in diagnosis and imaging modalities using radionuclides. General significance This review summarizes the various attempts that used GRP78 both in therapy (fighting cancer, viral and fungal infections) and diagnosis (imaging).