Endogenous ligands and drugs interact with the cell-surface proteome but hypothesis-free tracking of dynamic remodeling processes at the plasma membrane is challenging. We introduce cell surface thermal proteome profiling for comprehensive characterization of ligand-induced changes in protein abundances and thermal stabilities. We demonstrate drug binding to extracellular receptors, complexes and transporters, discover stimulation-dependent remodeling of T-cell receptor complexes and describe a competition-based approach to measure target engagement of GPCR antagonists.