This paper by Arthur Christopoulos and Terry Kenakin reviews the concept of allosterism in G protein-coupled receptors (GPCRs) and the mechanisms underlying allosteric interactions. The authors discuss the historical perspective on allosteric receptor models, including cooperative binding and multistate models of receptor action. They explore the molecular nature of allosterism, focusing on G protein-specific and ligand-specific receptor conformations. The paper also covers methods for detecting allosteric interactions, such as radioligand binding assays and receptor function assays, and discusses the potential pitfalls in these assays. The authors highlight the importance of allosteric modulators and their ability to act at multiple sites on the receptor, including the receptor-G protein interface and extracellular sites. They also examine the role of endogenous allosteric modulators and the complexing of GPCRs with other proteins. The review concludes with a discussion on the usefulness of allosteric modulators and the location of allosteric sites, emphasizing the need to understand the complex mechanisms of GPCR function.This paper by Arthur Christopoulos and Terry Kenakin reviews the concept of allosterism in G protein-coupled receptors (GPCRs) and the mechanisms underlying allosteric interactions. The authors discuss the historical perspective on allosteric receptor models, including cooperative binding and multistate models of receptor action. They explore the molecular nature of allosterism, focusing on G protein-specific and ligand-specific receptor conformations. The paper also covers methods for detecting allosteric interactions, such as radioligand binding assays and receptor function assays, and discusses the potential pitfalls in these assays. The authors highlight the importance of allosteric modulators and their ability to act at multiple sites on the receptor, including the receptor-G protein interface and extracellular sites. They also examine the role of endogenous allosteric modulators and the complexing of GPCRs with other proteins. The review concludes with a discussion on the usefulness of allosteric modulators and the location of allosteric sites, emphasizing the need to understand the complex mechanisms of GPCR function.