Cyclosporine (CsA) immunosuppressive therapy is confounded by a narrow therapeutic window and large intersubject variability. Trough-level monitoring cannot prevent the frequent occurrence of toxic side effects and graft rejection. Area-under-the-curve (AUC) monitoring affords better control of exposure of an individual patient to CsA, which is compensated for by a moderate increase in the number of blood samples. A linear pharmacokinetic model for CsA dosage adjustment using AUC measurements as feedback information decreased the incidence of delayed graft loss during the first month. This strategy failed, however, to lower the frequency of acute graft rejection despite a significant relationship between the probability of rejection and exposure to CsA (measured as average steady-state concentration). A nonlinear Michaelis-Menten model describes the relationship between oral dose rate and average steady-state concentration better than does a linear clearance model. Clinical utility of the nonlinear model remains to be proven.