Protein–protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional allostery implies that reverse modulation (i.e., from the ATP-binding site to the interaction and regulatory sites) must also be possible. Here, we review both the allosteric regulation of protein kinases and recent work describing how compounds binding at the ATP-binding site can promote or inhibit protein kinase interactions at regulatory sites via the reverse mechanism. Notably, the pharmaceutical industry has been developing compounds that bind to the ATP-binding site of protein kinases and potently disrupt protein–protein interactions between target protein kinases and their regulatory interacting partners. Learning to modulate allosteric processes will facilitate the development of protein–protein interaction modulators. Allostery is widespread in protein kinases.Allostery is defined as bidirectional communication between the regulatory site and the active site in protein kinases.Compounds binding at the ATP-binding site of protein kinases can enhance or disrupt protein–protein interactions.Metabolites can bind to the ATP-binding site and can potentially modulate physiological protein kinase interactions.Understanding allostery at the molecular level will enable the rational design of drugs with the desired allosteric effects.