The immune system is equipped with different checkpoints that ensure the maintenance of immune tolerance to self-antigens and the prevention of autoimmunity. One mechanism of peripheral tolerance involves the activity of specialized subsets of immune cells that are capable to regulate and/or suppress pro-inflammatory immune responses. These regulatory cells include multiple subsets that belong to both the adaptive and innate immune systems. This issue of Autoimmunity describes the role of the different types of immunoregulatory cells in autoimmune diseases.