The occurrence of bioactive pharmaceutical compounds in the aquatic environment is an emerging concern. Liquid chromatography, coupled with mass spectrometry (LC-MS) or tandem mass spectrometry (LC-MS-MS) using an electrospray ionization interface, is a crucial tool for addressing this issue. We review in this manuscript LC-MS and LC-MS-MS studies on waterborne PhACs in the last decade, including research activity in different geographical areas and the current status of the technology used for sample preparation, chromatographic separation, and mass spectrometric detection. A detailed overview on quality-control and quality-assurance (QC/QA) procedures is also presented, with emphasis on the need for a concerted approach to determine the numerical values associated with detection limits, and the use of low-level data qualifiers.