Significant progress has been made in understanding the principles of immune tolerance over the past decade. Previously, tolerance was primarily perceived as the complete elimination of autoreactive cells, adhering to the “ignorance is bliss” model. However, current insights reveal a more intricate understanding of tolerance. Scientists now recognize that while certain structures remain hidden from the immune system’s surveillance (evasion), and the most aggressive anti-self lymphocytes are eliminated (elimination), specific self-recognizing regulatory lymphocytes play a critical role in suppressing anti-self immune responses (engagement). The absence of this regulatory component disrupts the delicate equilibrium. Both central and peripheral tolerance mechanisms have been elucidated through animal models and are now being utilized to manipulate immune tolerance in humans. Various immunotherapeutic approaches are employed to treat autoimmune diseases and prevent immune rejection of allografts, showcasing some of the most promising applications of immune tolerance principles from research to clinical practice.