Several complementary approaches have been developed to discover modulators of protein–protein interactions (PPIs). This chapter provides a perspective on bioinformatic classifications of PPIs, which has led to a better understanding of which PPIs are more amenable to modulation. Next, workflows to target PPIs are outlined, including phenotypic screening and target-based approaches. Target-based approaches can be further categorized into structure-based design and target-based screening. The overview, benefits, and drawbacks of each workflow are discussed. Last, we illustrate two complementary computational methods to assess protein interfaces using the KIX protein.