This article describes the development, optimization, and validation of an analytical method for the simultaneous detection and identification of 73 pharmaceutical residues, covering various therapeutic groups, in both surface and wastewaters. The method is based on the simultaneous extraction of all target compounds by Solid Phase Extraction (SPE), using a hydrophilic−lipophilic balanced polymer followed by liquid chromatography tandem mass spectrometry, using a hybrid triple quadrupole-linear ion trap mass spectrometer (QqLIT). Quantitative analysis was performed using the 4000 Qtrap tandem mass spectrometer in Selected Reaction Monitoring (SRM) mode, monitoring two SRM transitions to fulfill EC guidelines, as well as to ensure an accurate identification of target compounds in the samples. Quantitation is performed by the internal standard approach, indispensable to correct matrix effects. Moreover, to obtain an extra tool for confirmation and identification of the studied pharmaceuticals, an Information Dependent Acquisition (IDA) experiment was performed, with SRM as the survey scan and an enhanced product ion (EPI) scan, at three different collision energies, as dependent scan. Compound identification was carried out by library search with a developed library, created by the infusion of standards, based on EPI spectra at the three collision energies. The main advantages of the developed method, besides high sensitivity (limits of detection ranging from 0.1−55 ng/L, depending on the matrix), selectivity, and reliability of results, are that all compounds are extracted in a single step, speeding up considerably sample preparation. Recoveries obtained were generally higher than 50% for both surface and wastewaters, with the exception of metronidazole (20−30%), salbutamol (33−43%), atorvastatin (40% in surface water), and nadolol (31% in surface water) that yielded lower but still acceptable recoveries. The overall variability of the method was below 15%, for all compounds and all matrixes tested. Finally, the method developed has been applied to the analysis of various influent and effluent wastewaters as well as river waters from Spain.