Hydrogen-deuterium exchange (HDX) is a powerful technique for studying protein motions in solution. It enables us to answer age-old questions connecting static protein structures to their movements in a more physiological environment. HDX is also an invaluable component of the integrated structural approach. It is particularly useful for challenging systems that are intractable by more traditional, higher resolution techniques. I will present recent work from the D’Arcy Laboratory to highlight the diverse applications of HDX. We have expanded the HDX toolbox to a diverse array of systems, from translational enzyme engineering and drug mechanisms, to the fundamental properties of large multi-protein and nucleic acid complexes. I will highlight the unique insights provided by HDX.