Several thousand tons of pharmaceuticals and their transformation products (metabolites and degradation products) are introduced into the environment each year. They affect both human health and the environment, therefore, analytical procedures enabling the determination of a wide range of pharmaceuticals at trace levels with minimal effort, time, and energy are required. Nowadays, hyphenated techniques are commonly applied in pharmaceutical analysis. This article provides a brief overview of the state-of-the-art and future trends in the determination of pharmaceutical residues and their transformation products with a focus on the most popular techniques in the field, such as ultra or high-performance liquid chromatography (UHPLC or HPLC) coupled with tandem mass spectrometry (MS/MS), quadrupole time-of-flight (QTOF), and a hybrid quadrupole/linear ion trap (QqLIT) in different environmental matrices (water, soil/sediment). Attention is paid to different aspects, benefits, and limitations of the application of UPLC and mass spectrometry–based techniques.