As an ER-resident molecular chaperone, Grp78/BiP can predominantly be found in the lumen and membrane of the ER. However, under certain conditions it is segregated to the cytosol, nucleus, mitochondria, the plasma membrane or the extracellular milieu including exosomes 6-10. A novel isoform of Grp78, termed Grp78va, was additionally identified in the mouse and human cytosol as the result of alternative splicing and alternative translation initiation 53. Evidence exists to demonstrate that ER stress-induced Grp78/BiP localization to the mitochondria and nucleus is implicated in cell survival pathways 116, 117. The surface expression of Grp78/BiP on tumor cells led to the suggestion that it might act as a signal transducer in malignity by promoting cancer stemness 118. In this context, several investigations provided evidence for the existence of a transmembrane variant of Grp78/BiP 116, 119, possibly by forming hydrophobic transmembrane helices 120. However, a recent study which used a combination of biochemical, mutational, FACS, and single molecule super-resolution imaging approaches, elucidated that Grp78/BiP devoid of a transmembrane domain predominantly exists as a peripheral protein on the plasma membrane in association with glycosylphosphatidylinositol-anchored cell surface proteins 121. The lack of Grp78/BiP on the cell surface of normal cells and adult organs 122, 123 led to the assumption of a specific cell surface transfer for Grp78/BiP in tumor cells 124. During ER stress, Grp78/BiP is actively secreted by cultured cells in vitro and in the peripheral circulation of healthy human individuals 125. Unfortunately, the molecular nature of the Grp78/BiP release is still unclear as HSPs in general lack the consensus signal for secretion. The mechanisms underlying its export might involve membrane-derived microparticles, the classical ER/Golgi secretory pathway, a non-classical exosomal protein secretory pathway 126 as well as necrotic or apoptotic mechanisms 127. Most recent investigations revealed that ER-stress induced translocation of Grp78/BiP to the cell surface includes KDEL receptor dispersion from the Golgi and suppression of the retrograde transport followed by an interaction between Grp78/BiP and glycosylphosphatidylinositol-anchored CD108, thereby regulating TGF-β signaling 128.