While protein characterisation is critical for continuing drug discovery and development, many techniques fall short of capturing the range of conformational dynamics that underpin the targeted protein activity. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) is a powerful tool for investigation of protein structural dynamics, particularly for membrane proteins in different mimetic environments. This measurement of intrinsic protein behaviour is invaluable in outlining pathogenic protein dynamics, protein–ligand profiles, and druggable protein centres that are often inaccessible in other structural techniques. This minireview will cover how recent advances have been applied to HDX-MS of membrane proteins and peptides widening the use of HDX for drug discovery.