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Liquid chromatography – tandem mass spectrometry (LC-MS/MS) is a powerful technique offering superior selectivity, sensitivity and flexibility for a diverse range of applications. This document describes the application of LC-MS/MS to analytical problems in environmental, clinical and forensic fields. LC-UV and LC-MS/MS methods were implemented and compared for the analysis of nitroaromatics, nitramines and nitrate esters in soil. Analysis of soils collected at detonation sites showed the presence and concentration of contaminants to be a function of parameters such as: time since detonation, type of charge employed, nature of detonation and size of charge used. Multi-increment (MI) sampling strategies recommended by the Environmental Protection Agency (EPA) were found to be impractical for wilderness environments. A structured grid strategy (SGS) is described which would allow representative sampling in complex terrain and enable the distinction between areas of high and low contamination, to more appropriately evaluate remediation needs. A new method was developed for the analysis of trace levels of buprenorphine, fentanyl and their metabolites in mice from low (<100 μL) plasma volumes. The method was fully validated, allowing an evaluation of current validation recommendations. The study highlighted the importance of using ion ratios as part of routine quantification, not just in method development. Another observation found that where suppression of internal standard signals resulted in reproducibility outside of standard limits (>20% RSD), if the signal was stable and within the linear range, the ratio of the analyte and internal standard signals was consistent and proportional to the concentration of analyte. This could impact current acceptance criteria for internal standard peak area reproducibility. A new hydrophilic interaction liquid chromatography (HILIC)-MS/MS method for the determination of cocaine and fentanyl, capable of indicating the smoked route of administration is described. The method was found to be highly selective and sensitive especially for basic and highly polar acidic species. Challenges facing traditional reverse phase (RP) LC separation of the highly hydrophilic compounds ecgonine, anhydroecgonine methyl ester and anhydroecgonine are eliminated in hydrophobic interaction (HI) mode through the incorporation of multiple retention mechanisms. The method could be easily adapted to the separation of other acidic, basic or highly polar drug compounds where RP separation has previously not been possible.