Experimental models of autoimmune diseases have revealed the disease protective role of heat shock proteins (HSPs). Both the administration of exogenous extracellular, mostly recombinant, HSP and the experimental co-induction of endogenous intracellular HSP in models have been shown to lead to production of disease protective regulatory T cells (Tregs). Similar to HSP taken up from extracellular bodily fluids, due to stress-related autophagy upregulated HSP also from intracellular sources is a major provider for the major histocompatibility class II (MHCII) ligandome; therefore, both extracellular and intracellular HSP can be prominent targets of Treg. The development of therapeutic peptide vaccines for the restoration of immune tolerance in inflammatory diseases is an area of intensive research. In this area, HSPs are a target for tolerance-inducing T-cell therapy, because of their wide expression in inflamed tissues. In humans, in whom the actual disease trigger is frequently unknown, HSP peptides offer chances for tolerance-promoting interventions through induction of HSP-specific Treg. Recently, we have shown the ability of a bacterial HSP70-derived peptide, HSP70-B29, to induce HSP-specific Tregs that suppressed arthritis by cross-recognition of their mammalian HSP70 homologues, abundantly present in the MHCII ligandome of stressed mouse and human antigen-presenting cells in inflamed tissues.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.