Legend has it that if you ask an Irishman for directions, he will suggest a landmark a mile beyond the destination. In a not too dissimilar fashion, Dr. Tom Starzl, whose mother was Irish, recommended dosing cyclosporine to nephrotoxicity and then reducing the dose. This was before therapeutic monitoring (TDM) was introduced for cyclosporine. It was an inspired observation because it was also before the drug’s mechanism of action was known. Subsequent studies showed that both the desired and undesired effects of cyclosporine were related to its inhibition of calcineurin phosphatase and thus nephrotoxicity was an external marker of the level of immunosuppression. With the advent of assays for cyclosporine, its pharmacokinetic profile was found to be extremely variable and TDM was recommend. Unfortunately drug trough levels, which were used to guide treatment for almost 2 decades, were found not to correlate with either total drug exposure or clinical outcomes.