Mass spectrometry (MS) plays a number of key roles in the discovery and development phases for modern pharmaceutical compounds, ranging from the assessment of protein–ligand binding to biomarker discovery. Historically, however, MS has had a relatively limited role in the drug discovery process in comparison to high-throughput fluorescence and radiometric screens. This picture may be changing, however, as many presumptive protein targets are coupled to human disease pathways through specific protein–protein interactions and protein conformations, rather than enzyme activities. This fact will likely drive the development of high-throughput analytical tools that put a stronger emphasis on the structural information content produced in a screen. Here we summarize recent developments surrounding ion mobility-mass spectrometry (IM-MS), one such MS-based tool that is capable of rapidly measuring changes in protein structure, oligomeric state, and binding stoichiometry from complex mixtures at relatively low concentrations.