Therapeutic drug monitoring (TDM) plays an important role in ensuring optimal drug therapy and has become increasingly important in clinical practice. In the first part of this review article, we provide an overview over the definition of and developments in TDM in clinical medicine, including the classification of potential target drugs, typical sample matrices, different sample pretreatment and standard detection methods. In the second part, the potential and superiority of surface-enhanced Raman spectroscopy (SERS) as analytical method is introduced, i.e. the specificity of molecular fingerprinting with simultaneous trace sensitivity due to the application of robust plasmonic-active nanostructured sensing surfaces. Finally, we discuss the direct combination of SERS with TDM including essential sample pretreatment procedures.