The β₂-adrenergic receptor (β₂AR) is perhaps the most thoroughly investigated of all G-protein-coupled receptors. Although the classical pathway of β₂AR signaling involves agonist-promoted binding of the receptor to the heterotrimeric guanosine triphosphate-binding protein G_s, activation of adenylyl cyclase, and production of cyclic adenosine monophosphate (cAMP), current evidence suggests that β₂AR signaling is regulated by interaction with multiple proteins. These interactions fall into 3 major groups: guanosine triphosphate-binding proteins such as G_s and G_i; protein kinases such as the cAMP-dependent protein kinase, protein kinase C, G-protein-coupled receptor kinases, and tyrosine kinases; and adaptor proteins such as arrestins, A-kinase anchoring proteins, and the Na⁺/H⁺-exchanger regulatory factor. This review discusses these various interactions with particular emphasis on their role in regulating β₂AR signaling and trafficking. (J Allergy Clin Immunol 2002;110:S229-35.)