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A central dogma of G protein-coupled receptor (GPCR) pharmacology has been the concept that unlike agonists, antagonist ligands display equivalent affinities for a given receptor, regardless of the cellular environment in which the affinity is assayed. Indeed, the widespread use of antagonist pharmacology in the classification of receptor expression profiles in vivo has relied upon this ‘antagonist assumption'. However, emerging evidence suggests that the same gene-product may exhibit different antagonist pharmacological profiles, depending upon the cellular context in which it is expressed—so-called ‘phenotypic' profiles. In this commentary, we review the evidence relating to some specific examples, focusing on adrenergic and muscarinic acetylcholine receptor systems, where GPCR antagonist/inverse agonist pharmacology has been demonstrated to be cell- or tissue-dependent, before going on to examine some of the ways in which the cellular environment might modulate receptor pharmacology. In the majority of cases, the cellular factors responsible for generating phenotypic profiles are unknown, but there is substantial evidence that factors, including post-transcriptional modifications, receptor oligomerization and constitutive receptor activity, can influence GPCR pharmacology and these concepts are discussed in relation to antagonist phenotypic profiles. A better molecular understanding of the impact of cell background on GPCR antagonist pharmacology is likely to provide previously unrealized opportunities to achieve greater specificity in new drug discovery candidates.