Heat shock proteins (HSPs) are a large family of inducible but also ubiquitously and constitutively expressed protein chaperones involved in assisting protein folding and unfolding in the cells. The realization of the immunological significance of HSPs came from the observation that tumor cell-derived HSPs could immunize against tumors, although there were no structural differences between HSPs from normal cells and from cancer cells. Studies of this puzzle have uncovered two unique immunological properties of HSPs. One is their ability to associate and present antigenic fingerprints/peptides of cells to MHC antigens. The other is their ability to activate dendritic cells (DCs), which are the most efficient antigen-presenting cells. These surprising immunological attributes of HSPs are now the basis for a number of already completed clinical trials for cancer immunotherapy. Because DCs orchestrate both innate and adaptive immunity, the findings that HSPs can modulate the functions of DCs may have fundamental implications. We hypothesize that HSPs are at the forefront in counterbalancing T-cell tolerance to tumor-associated antigens and thus play pivotal roles in antitumor immunity in vivo.