G protein-coupled receptors (GPCRs) have historically been associated with signalling events driven from the plasma membrane. More recently, signalling from endosomes has been recognized as a feature of internalizing receptors. However, there was little consideration given to the notion that GPCRs can be targeted to distinct subcellular locations that did not involve an initial trafficking to the cell surface. Here, we focus on the evidence for and the potential impact of GPCR signalling specifically initiated from the nuclear membrane. We also discuss the possibilities for selectively targeting this and other internal pools of receptors as novel venues for drug discovery.