The third cytoplasmic loop is a crucial site of physical contact between some G protein-coupled receptors (GPCRs) and their respective G proteins. However, interactions not only occur among these proteins but also involve a number of additional protein binding partners. Modulation of these protein-protein interactions may represent an important new avenue of pharmacotherapy through which signaling of GPCRs can be modulated. In the current issue of Molecular Pharmacology, Liu et al. (p. 371) report that dopamine D(2) receptors interact with the Ca(2+) binding protein S100B. Using the third intracellular loop of the dopamine D(2) receptor as bait in a bacterial two-hybrid system, S100B was determined to be a potential binding partner. They used pull-down assays both in vitro and in vivo to confirm the interaction and define its specificity. Neither the D(3) nor the D(4) receptor expresses the motif conferring the interaction, and peptides based on the third intracellular loop of the D(3) receptor did not pull down S100B. Some groups might stop there, but Liu and colleagues moved on to demonstrate colocalization of the D(2) receptor and S100B by immunostaining. Functional assays were then used to show that coexpression of S100B with the D(2) receptor increases the ability of D(2) receptors to activate ERK and to inhibit adenylyl cyclase. These data suggest that S100B coexpression may serve as an important mediator of D(2) receptor signaling efficacy in the brain. These interactions contribute to cellular, regional, and developmental differences in D(2) receptor activation.