Starting with a crystal structure of a macromolecule, computational structural modeling can help to understand the associated biological processes, structure and function, as well as to reduce the number of further experiments required to characterize a given molecular entity. In the past decade, two classes of powerful automated tools for investigating the binding properties of proteins have been developed: the protein–protein docking program ClusPro and the FTMap and FTSite programs for protein hotspot identification. These methods have been widely used by the research community by means of publicly available online servers, and models built using these automated tools have been reported in a large number of publications. Importantly, additional experimental information can be leveraged to further improve the predictive power of these approaches. Here, an overview of the methods and their biological applications is provided together with a brief interpretation of the results.