It is now generally accepted that rhodopsin-like, family A G protein-coupled receptors (GPCRs) possess quaternary structure and can form dimers or higher-order oligomers. It is less clear if these are constitutive interactions or whether their organisational structure can vary during their life history. By developing an endoplasmic reticulum (ER) trapping strategy, based on addition of the C-terminal 14 amino acids of the alpha2C-adrenoceptor to the C-terminal tail of other GPCRs that normally traffic successfully to the cell surface, we were able to demonstrate that such a modified form of the chemokine CXCR1 receptor became retained in the ER. This modified receptor acted as a ‘dominant negative’ and prevented cell surface delivery of wild type forms of both the CXCR1 and CXCR2 receptors. However, it was without effect on trafficking of alpha1-adrenoceptors, which do not interact with the CXCR1, (Wilson et al., 2005). Such observations indicate that GPCR-GPCR interactions already occur during protein synthesis/maturation and prior to cell surface delivery. alpha1-adrenoceptors also possess quaternary structure and mutations, selected based on likely protein- protein contact sites, determined by receptor fragment interaction mapping studies (Carrillo et al., 2004), that modulate the effectiveness of protein-protein interactions can result in incomplete receptor maturation and trapping of the complex in the ER/Golgi, even though bi-molecular fluorescence complementation (BiFC) studies indicate that protein-protein interactions are not ablated (Lopez-Gimenez et al., 2007). BiFC approaches can also be employed to show that wild type and ligand-rescued mutant alpha1-adrenoceptors traffic to the cell surface as dimers/oligomers. A wide range of studies have indicate that GPCR hetero-dimerisation can modulate the function and pharmacology of GPCRs. In part, this involves allosteric effects across the dimer interface, such that ligand that have no inherent affinity for a GPCR can regulate the function of the GPCR if it forms a hetero-dimer with a GPCR that binds the ligand in question (Ellis et al., 2006). Combinations of BiFC employing GPCRs that constitutive internalise, such as the alpha1-adrenoceptor, and fluorescent ligands that bind and co-internalise, have also demonstrated that at least certain GPCRs internalise from the cell surface into the cell as dimers/oligomers (Lopez-Gimenez et al., 2007). Such studies also indicate that GPCR dimers interact with beta-arrestins but it remained to be established if the recently reported dimerisation of beta-arrestins is integral to this process.