Hydrogen–deuterium exchange mass spectrometry (HDX-MS) is a powerful tool for mapping the interactions between antibodies and antigens. Automation, coupled with a suite of sophisticated enzymatic and analytical tools, has enabled HDX-MS epitope mapping of increasingly complex antigenic targets in screens of dozens of antibodies. When information about epitopes and allosteric changes from HDX-MS is considered in the context of binding and functional datasets, a deeper understanding of how antibodies achieve their therapeutic outcomes is achieved. These insights help guide the development of novel immunotherapeutics and vaccines. In this chapter, we discuss the key steps and considerations involved in designing and executing an HDX-MS epitope screening experiment.