Over the past decade, our laboratory has developed a secreted heat shock protein (HSP), chaperone gp96, cell-based vaccine that generates effective anti-tumor and anti-infectious immunity in vivo. Gp96-peptide complexes were identified as an extremely efficient stimulator of MHC I-mediated antigen cross-presentation, generating CD8 cytotoxic T-lymphocyte responses detectable in blood, spleen, gut and reproductive tract to femto-molar concentrations of antigen. These studies provided the first evidence that cell-based gp96-Ig-secreting vaccines may serve as a potent modality to induce both systemic and mucosal immunity. This approach takes advantage of the combined adjuvant and antigen delivery capacity of gp96 for the generation of cytotoxic immunity against a wide range of antigens in both anti-vial and anti-cancer vaccination. Here, we review the vaccine design that utilizes the unique property/ability of endoplasmic HSP gp96 to bind antigenic peptides and deliver them to antigen-presenting cells.