<p>Monitoring dynamic changes in drugs and their metabolites is essential for basic research, preclinical evaluation, and clinical applications. Surface-enhanced Raman spectroscopy (SERS) has shown great promise in therapeutic drug monitoring due to its high sensitivity, minimal sample consumption, non-destructive analysis, unique molecular fingerprints, and low cost. This review summarizes recent progress in SERS-baseand D–E]. For example,d drug monitoring, emphasizing novel substrate designs that improve detection sensitivity and selectivity. Key challenges, including poor signal reproducibility and interference from complex biological matrices, are discussed together with emerging strategies such as digital colloid-enhanced Raman spectroscopy, enrichment-based detection, microfluidic SERS, hybrid analytical platforms, and machine learning-assisted analysis. These approaches effectively address the limitations of conventional SERS and enhance analytical performance. Finally, future perspectives are outlined, highlighting the potential of integrating SERS with advanced technologies for targeted drug delivery, personalized therapy, and improved clinical outcomes. </p> Graphical abstract <p></p>