The structural analysis of viruses is often a complex task. In many cases, the details of the viral architecture, especially for enveloped viruses, are limited to low-resolution techniques such as electron microscopy. These structural proteins and assemblies of viruses often populate multiple conformational states and undergo dramatic structural changes, making them difficult to study by most structural methods. They also frequently include highly dynamic regions that are of key functional importance. Many viruses present large surface glycoproteins, which have also proved to be challenging for structural biology due to the intrinsic flexibility and heterogeneity of the glycan decorations. Over the past two decades, hydrogen deuterium exchange coupled to mass spectrometry (HDX-MS) has provided a wealth of information on many diverse viral proteins, glycoproteins, and complexes, in many cases, in multiple conformational states. Here, we describe the methodology for using HDX-MS to investigate the rich structural dynamics of viral systems, and we briefly review the type of systems that have been examined through this type of approach. Though the technique is relatively simple, several potential pitfalls exist at both the sample preparation and the data analysis stage that investigators should be aware of for obtaining reliable data.