Multidrug immunosuppressive protocols have increased short-term patient and graft survival rates from 50% to 90% in the past two decades. Unfortunately, chronic graft rejection still remains the main cause of long-term failure and patients must undergo lifelong immunosuppression. The severe side effects such as life-threatening infections, secondary malignancies, and cardiovascular dysfunction all together include roughly 50% of deaths among kidney transplant patients with functioning grafts. Therefore, it should be of crucial importance to reduce immunosuppression and seek induction of specific tolerance to donor alloantigens. Several investigations have suggested that the acquisition of tolerance to self and/or foreign antigens is dependent on the number and function of naturally occurring and acquired regulatory T cells, which can control all aggressive T cells. The regulatory T cells together with their receptors, costimulatory molecules, cytokines, chemokines, and growth factors all contribute to maintain an equilibrium between aggressive and suppressive effector immune responses. As a consequence of increased knowledge, new immunosuppressive approaches based on either alloantigen-specific regulatory T-cell expansion in vivo or in vitro have been proposed to achieve donor-specific transplantation tolerance in kidney allograft recipients. This contribution attempted to summarize knowledge about regulatory T cells and developing methods to induce specific tolerance in kidney transplantation.