Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase (TDO), programmed death-ligand 1 (PD-L1), and forkhead box P3 (Foxp3). These proteins are highly expressed in professional antigen-presenting cells under various physiological conditions, such as inflammation and stress. Therefore, self-reactive T cells that recognize such targets may be activated due to the strong activation signal given by their cognate targets. The current review describes the existing knowledge regarding these self-reactive anti-Tregs, providing examples of antigen-specific anti-Tregs and discussing their possible roles in immune homeostasis and their potential future clinical applications.