Over the last 60 years extensive development has occurred in the-pharmacological treatment of mental illnesses with currently over 40 different-compounds being prescribed. Antipsychotic drugs (APs) are today amongst the most commonly prescribed drug classes with second generation or atypical APs accounting for the-majority of prescriptions worldwide. As noncompliance is a common problem amongst patients treated with APs, these drugs are frequently subject to therapeutic drug monitoring (TDM). LC-MS techniques have facilitated the detection of these drugs which are frequently associated with very low blood concentrations particularly after IM depot injections. Multiple methods for the detection and quantification of APs in human biological specimens have been published using LC-MS, particularly in the last decade, as this instrumentation has been available for routine laboratories. This chapter reviews published multianalyte methods and highlights the important-criteria when developing an analytical method for the detection of APs, potential pitfalls, and the importance of appropriate method validation, in order to assure reproducibility of results.