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High-performance liquid chromatography coupled with tandem mass spectrometry is commonly used for quantitation of analytes in biological matrices, because of the selectivity, sensitivity, and high throughput offered by this technique. However, the presence of both suppression and enhancement of ionization (SEI) by matrix components is an increasingly recognized impediment to accurate results. The existence of SEI indicates that ionization efficiency is a result of the chemical environment seen by both the analyte and internal standard during ion formation. SEI is influenced by the type and the make of ion source used, mobile-phase composition, extent of sample preparation, and the ability to chromatographically separate other compounds that may influence ionization of the analyte and/or internal standard. A comprehensive review of the phenomenon of SEI in high-performance liquid chromatography coupled with tandem mass spectrometry was conducted, and a summary of salient papers relating to therapeutic agents in biological matrices is presented. Suggestions for approaches to minimize, normalize, or assess SEI and its deleterious effect on accuracy and sensitivity, and hence the validity of quantitative results, are provided. Consideration is also given to a strategy to test for SEI, including the number of samples from different sources that are required to adequately test for SEI.