Protein phosphorylation is a key event in signal transduction pathways. When upstream signals are stimulated, protein kinases are activated and phosphorylate their substrates, modulating their localization, conformation, and activity. In some cases, phosphorylated substrates become recognizable to other proteins-such interactions transduce and propel the signal onward. Certain domains specifically recognize phosphorylated residues of proteins, regulating cell growth and differentiation. Because the proteins that contain these domains also mediate diseases that are caused by dysregulated signal transduction, small molecules that inhibit such motifs are attractive candidates for the treatment of diseases, such as cancer. In this review, we summarize the domains that recognize phosphorylated proteins, particularly serine- and threonine-phosphorylated sequences in target proteins. In addition, we introduce a high-throughput screen that we developed to identify small-molecule inhibitors of phosphorylation-dependent protein-protein interactions. An example is presented, and the potential uses of this system are discussed.