Since its introduction 20 years ago, cyclosporine (CyA), a powerful immunosuppressant with a narrow therapeutic window, remains the cornerstone of many drug regimens in renal transplantation. However, attempts to balance its therapeutic value with its pleiotropic side effects continue to challenge clinicians. To address the wide intraindividual and interindividual differences in absorption, distribution, metabolism, and elimination of the oil-based formulation of CyA (Sandimmune), a microemulsion (Neoral) was introduced; it displayed better absorption and lower intraindividual variability. Neoral also improves the utility of therapeutic monitoring of CyA to estimate exposure to the drug and predict patient outcomes. Drug monitoring techniques are undergoing continual refinement: today, a limited sampling strategy--C2 monitoring--shows great promise as a comparatively simple, safe, and effective method to optimize patient outcomes during both short-term and maintenance CyA therapy. However, it is not clear whether this method is useful for treatment optimization with generic formulations of CyA. Although generic substitutes meet federal bioequivalence criteria, they may not display the same pharmacokinetic properties. Further, preliminary data have shown a 10% lower 1-year graft survival rate among patients treated with generic versus Neoral CyA. Current challenges in optimizing CyA therapy include determining pretransplant patient characteristics relevant to selection of the appropriate exposure or the development of a Bayesian forecasting technique that predicts dose adjustments necessary to achieve the optimal drug regimen during the critical period immediately posttransplant.