Proteins are the workhorses of cells to carry out sophisticated and complex cellular processes. Such processes require a coordinated and regulated interactions between proteins that are both time and location specific. The strength, or binding affinity, of protein–protein interactions ranges between the micro- and the nanomolar association constant, often dictating the molecular mechanisms underlying the interaction and the longevity of the complex, i.e., transient or permanent. In consequence, there is a need to quantify the strength of protein–protein interactions for biological, biomedical, and biotechnological applications. While experimental methods are labor intensive and costly, computational ones are useful tools to predict the affinity of protein–protein interactions. In this chapter, we review the methods developed by us to address this question. We briefly present two methods to comprehend the structure of the protein complex derived by either comparative modeling or docking. Then we introduce BADOCK, a method to predict the binding energy without requiring the structure of the protein complex, thus overcoming one of the major limitations of structure-based methods for the prediction of binding affinity. BADOCK utilizes the structure of unbound proteins and the protein docking sampling space to predict protein–protein binding affinities. We present step-by-step protocols to utilize these methods, describing the inputs and potential pitfalls as well as their respective strengths and limitations.