Heat-shock proteins (HSPs) perform opposing functions in autoimmune arthritis. HSP-specific T cells drive the progression of adjuvant arthritis (AA), an experimental model of autoimmune arthritis. However, HSP-specific T cells can also have a regulatory phenotype, controlling arthritogenic T cells and inhibiting AA progression. This manuscript reviews the use of DNA vaccines coding for HSPs to analyse the role of these proteins in the regulation of arthritis. Recent studies suggest that HSPs participate in the control of pathological autoimmunity. Indeed, DNA vaccines coding for HSPs can be used to activate these HSP-specific built-in regulatory mechanisms. Thus, DNA vaccines coding for HSPs may serve not only as tools for the dissection of immunoregulatory mechanisms, but also as agents for the treatment of autoimmune disorders.