Autoimmune diseases, including inflammatory arthritis, are characterized by a loss of self-tolerance, leading to an excessive immune responses and subsequent ongoing inflammation. Current therapies are focused on dampening this inflammation, but a permanent state of tolerance is seldom achieved. Therefore, novel therapies that restore and maintain tolerance are needed. Tregs could be a potential target to achieve permanent immunotolerance. Activation of Tregs can be accomplished when they recognize and bind their specific antigens. HSPs are proteins present in all cells and are upregulated during inflammation. These proteins are immunogenic and can be recognized by Tregs. Several studies in animal models and in human clinical trials have shown the immunoregulatory effects of HSPs and their protective effects in inflammatory arthritis. In this review, an overview is presented of the immunomodulatory effects of several members of the HSP family in general and in inflammatory arthritis. These effects can be attributed to the activation of Tregs through cellular interactions within the immune system. The effect of HSP-specific therapies in patients with inflammatory arthritis should be explored further, especially with regard to long-term efficacy and safety and their use in combination with current therapeutic approaches.