The regulation of the immunosuppressive therapy after kidney transplantation is the most complex aspect of the management of transplanted patients. Every day the transplant clinician is challenged by need to provide a sufficient immunosuppression to avoid or reduce the risk of rejection without exposing the patient to the risk of developing opportunistic infections or malignancy or toxic side effects. The safety and efficacy profile of immunosuppressive therapy is limited within a narrow therapeutic window whose borders are represented by two clinical conditions such as rejection and drug-related toxicity. The availability of several different drugs allows the clinicians to make multiple choices to individualize treatments according to the specific needs of a single patient. Pharmacokinetic monitoring of the immunosuppressive drugs is an important element in the management of these patients but cannot be considered as the unique driving factor and must be integrated with a careful surveillance and evaluation of all drug-related side effects.