Heat-shock proteins (HSPs) are the most abundant and ubiquitous soluble intracellular proteins. Members of the HSP family bind peptides, including antigenic peptides generated within cells. HSPs also interact with antigen-presenting cells (APCs) through CD91 and other receptors, eliciting a cascade of events that includes representation of HSP-chaperoned peptides MHC, translocation of NF-kappaB into the nuclei, and maturation of dendritic cells. These consequences point to a key role of HSPs in fundamental immunologic phenomena such as activation of APCs, indirect presentation (or crosspriming) of antigenic peptides, and chaperoning of peptides during antigen presentation. The properties of HSPs also allow them to be used for immunotherapy of cancers and infections in novel ways. This paper reviews the development and clinical trial progress of vitespen, an HSP peptide complex vaccine based on tumor-derived glycoprotein 96.