Demonstration of target binding is a key requirement for understanding the mode of action of new therapeutics. The cellular thermal shift assay (CETSA®) has been introduced as a powerful label-free method to assess target engagement in physiological environments. Here, we present the application of live-cell CETSA® to different classes of integral multi-pass transmembrane proteins using three case studies: the first showing a large and robust stabilization of the outer mitochondrial five-pass transmembrane protein TSPO, the second being a modest stabilization of SERCA2, and the last describing an atypical compound-driven stabilization of the GPCR PAR2. Our data demonstrated that using modified protocols with detergent extraction after the heating step, CETSA® can reliably be applied to several membrane proteins of different complexity. By showing examples with distinct CETSA® behaviors, we aim to provide the scientific community with an overview of different scenarios to expect during CETSA® experiments, especially for challenging, membrane bound targets.