Therapeutic drug monitoring of immunosuppressive drugs, namely, cyclosporine A, tacrolimus, sirolimus, everolimus, and mycophenolic acid, is an accepted measurement service that strongly supports transplantation medicine worldwide. During the past twenty years, ligand-binding assays lost their predominance, and liquid chromatography with tandem mass spectrometry–based analysis platforms gained importance. This transformation step is now finished, with both solutions in routine use. However, comparability between these methodologies is limited since traceability of the measurements to higher-order reference materials and reference standards is currently incomplete—a frequent situation in drug monitoring and toxicology. The chapter will provide an overview of the development of this... instrumental analysis field over the past twenty years.