Drugs targeting the orthosteric, primary binding site of G protein?coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. In this paper we report the crystal structure of the prototypic ?<
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2<
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-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor?s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an ?-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for ?<
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2<
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- over the ?<
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1<
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-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.