Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) constitutes now a key instrumental component of medical laboratory centres and has greatly facilitated the development of a considerable number of drugs assays for Therapeutic Drug Monitoring (TDM). The concept of TDM implies the measurement of concentrations of certain drugs in patients' blood, followed by dosage individualization based on patients' circulating exposure, targeting a pre-defined concentration range. This approach aims at increasing the likelihood of achieving therapeutic efficacy, while reducing the risk of toxicity. TDM can contribute to the rational individualization of critical drug treatments, notably antivirals, antibiotics, antiepileptics, psychotropic drugs and targeted anticancer agents, in the context of growing efforts towards personalized medicine. This article aims at reviewing the basic concepts, the role and the perspectives of evolution of TDM. It presents selected examples of clinical applications and gives some insights on how TDM is definitely benefiting from the tremendous development of LC-MS/MS techniques.