Kidney transplantation is the best treatment option in chronic kidney disease patients. Despite the new potent immunosuppressants, the long-term graft survival has not significantly improved. This is a rather complex issue with interrelationship between pretransplant donor-recipient variables, recipient post-transplant perioperative non/immunological factors, the combination/dose of maintenance immunosuppression and the general noncompliance of the patient. The recipients with an increased immunological risk should be maintained on triple therapy with steroids, preferably tacrolimus (Tac) or cyclosporine (CsA) plus mycophenolate mofetil (MMF). Eventual calcineurin inhibitor (CNI) minimization should be coupled with either protocol biopsies or frequent biochemistry monitoring including periodical assessment of anti-human leukocyte antigen and donor-specific antibodies. Recipients with standard immunological risks may be considered for as low as possible triple immunosuppression (steroids, Tac/CsA, MMF) after a period of 6 - 12 months. In cases of CNI minimization, a modification with a higher dose of the other two drugs in the triple therapy combination might be considered. The nonadherence to the prescribed maintenance therapy should be regularly checked-up. In conclusion, antibody induction, MMF, steroids and low-dose Tac/CsA should be the mainstream therapy in majority of patients. The short- and mid-term encouraging results for CNI minimization/withdrawal seem to correspond to recent findings of chronic antibody-mediated rejection, and long-term results need further evaluation.