Despite the introduction of new immunosuppressive agents and excellent 1-year graft survival rates, acute and chronic rejection and a variety of side effects still result in significant morbidity and cost to transplant recipients and the health care system. The tremendous intra-and interindividual variability resulting from a failure to individualize immunosuppression is one of the major, and potentially modifiable, causes. With the introduction of the cyclosporine microemulsion formula, a new interest has risen in the use of limited sampling or single postdose concentration measurements instead of predose trough levels. Also, for tacrolimus, trough levels may not be optimal for monitoring and interest in limited sampling strategies for estimation of drug exposure is increasing. For mycophenolate mofetil, which is used as a fixed-dose drug in most centers, data are accumulating regarding the use of trough levels or area under the curve monitoring to optimize the therapy. Sirolimus, owing to its novel mechanism of action, acts synergistically and permits dose reduction of calcineurin inhibitors. In addition, sirolimus has a distinct side-effect profile. However, sirolimus is a critical-dose drug for which therapeutic drug monitoring strategies are being developed. Knowledge of the pharmacokinetic/pharmacodynamic interactions between immunosuppressive drugs, which behave as critical-dose drugs, is likely to help clinicians provide optimal immunosuppression to achieve not only excellent short-term but also superior long-term results with minimal toxicity.