Cyclosporine was introduced into clinical transplantation as an immunosuppressive agent 20 years ago. Cyclosporine is a critical dose drug with a narrow therapeutic index and requires monitoring through blood levels to avoid rejection through underexposure or toxicity through overexposure. Traditional monitoring was by measuring the trough level taken 12 hours after an oral dose, but the results correlated poorly with drug dose, toxicity, and outcome. Monitoring cyclosporine by calculating total drug exposure correlated better with outcome but was time consuming and labour intensive. An abbreviated measure of exposure over the first 4 hours after administration was found to predict outcome and allow dose adjustment. This was based on the observation that the majority of variability in the absorption of the drug was during the first 4 hours after administration--the absorption phase--and this was not reflected in the trough level. Cyclosporine exerts its immunosuppressive action by inhibition of calcineurin. The peak of this inhibition occurs during the peak concentration of the drug, which occurs during the absorption phase. On the basis of the fact that as a single time point the 2-hour level was the best surrogate marker of the maximum level, a strategy for monitoring by 2-hour levels (C2) evolved. It was shown in all organ types to be the best single point predictor of exposure and has led to an improvement in outcome both in de novo and in maintenance transplant patients.