Kidney transplantation has become the treatment of choice in end-stage chronic renal failure since it significantly improves both the quality of life and the life duration of affected patients, when compared with dialysis. Some of these better results that were observed over the last thirty years are obviously due to significant improvements in the quality of immunosuppression. In the first part of this chapter, the allo-immune response is schematically described regarding the various signals. Then, the mechanisms of action of the available or future immunosuppressive therapies are described in the same order as the allo-immune response. In the third part, the various combinations of immunosuppressive regimens are presented from a historical perspective, outlining not only the positive aspects of each class of drugs but also their side effects and consequences on the practical use of immunosuppression over time. Finally, a brief review of current and future perspectives regarding the improvement of both efficacy and tolerability of immunosuppression in kidney transplantation is presented.