The 3D structure of a protein defines not only its size and shape but also its function. But the relationship between structure and function is anything but simple. As such, designing drugs to regulate the functions of these proteins remains an arduous goal. Integrative structural biologists—a diverse collection of scientists from various fields such as cell biology, protein engineering, and computational science—use multiple sources of data and a combination of methods to answer intractable structural biology questions. Recent advancements in technology have allowed the structures of macromolecules to be deciphered at greater and greater speeds. However, as new methods are developed, there are challenges to overcome with respect to their integration into the growing suite of applications. Included in this booklet are articles from the Science family of journals, as well as from the booklet sponsor, detailing the analytical tools available and how they can be applied to solve some of the most complex challenges in the field.