Heat-shock proteins are chaperones for proteins including tumor antigens. Heat-shock protein gp96, also known as glucose-regulated protein grp94, is the primary chaperone of the endoplasmic reticulum and a natural adjuvant for priming the innate and adaptive immune system. By transfecting tumor cells with a genetically modified secretory form of gp96, the tumor cells are transformed into vaccine cells. Gp96 vaccines in murine studies trigger robust innate and antigen-specific cellular immune responses and cause tumor rejection followed by long-lasting tumor immunity. The authors briefly review here the generation of cytotoxic T lymphocyte responses by gp96 and the most up to date clinical data in the use of gp96-based cancer vaccines.