Glycoprotein　96　(gp96)　is　a　highly　conserved　and　ubiquitous　glycoprotein　that　belongs　to　the　heat　shock　protein　90　(HSP90)　family.　It　comprises　4　domains:　N-terminal　domain　(NTD),　middle　domain　(MD),　C-terminal　domain　(CTD)　and　charged　linker　region　(CR).　Each　domain　performs　a　specific　function.　NTD　containing　the　nucleotide　binding　site　interacts　with　and　hydrolyzes　ATP.　MD　is　involved　in　client　protein　recognition,　and　is　the　site　of　constitutive　dimerization.　The　ATP　hydrolytic　activity　of　NTD　requires　cooperative　action　of　CR　and　MD.　The　schematic　representation　of　gp96　topology　is　shown　in　the　main　text.　An　increased　expression　of　gp96　has　been　reported　in　multiple　cancers.　Its　upregulation　in　tumors　is　closely　correlated　with　poor　prognosis　and　decreased　overall　survival　of　patients,　indicating　that　gp96　serves　as　a　potential　diagnostic　and　prognostic　biomarker.　As　a　chaperone　protein　gp96　directs　the　folding　and/or　assembly　of　secreted　and　membrane　proteins.　It　has　a　limited　client　protein　profile　that　is　involved　in　key　processes　linked　with　the　hallmarks　of　cancer.　Previous　studies　have　shown　that　cellular　gp96　physically　interacts　with　and　directs　the　folding　and　assembly　of　several　client　proteins,　including　insulin-like　growth　factors　(IGF),　integrins,　epidermal　growth　factor　receptor-2　(HER2)　and　Wnt　co-receptor　LRP6,　which　are　involved　in　the　regulation　of　cell　multiplication,　normal　tissue　differentiation,　cancer　progression　and　metastasis.　It　has　been　found　that　gp96　was　only　expressed　on　cell　surface　of　malignant　tumor　but　not　benign　tissues.　Cell　membrane　gp96　is　closely　associated　with　cancer　cell　proliferation,　invasion,　and　metastasis.　We　further　demonstrated　that　gp96　on　cell　membrane　interacts　with　HER2,　urokinase-type　plasminogen　activator-receptor　(uPAR)　or　ER-alpha　36.　Targeting　gp96　by　siRNA　or　a　monoclonal　antibody　for　gp96　led　to　decreased　cell　growth　and　invasion,　increased　apoptosis　in　vitro,　and　suppression　of　tumor　growth　in　vivo,　validating　cell　membrane　gp96　as　a　therapeutic　target.　At　present,　the　selective　small-molecule　inhibitors　(NECA　and　PU-WS13),　a　gp96-specific　monoclonal　antibody　(W9mAb),　and　an　inhibitory　gp96-targeted　polypeptide　(p37)　are　under　development　and　their　potential　applications　in　the　tumor　targeting　therapy　are　highlighted　in　this　review.