Recent data have expanded on well‐established roles for G protein‐coupled receptors by demonstrating the presence of GPCRs and the activities of their cognate pathways within certain cellular nuclei. As other groups have shown, sphingosine 1‐phosphate receptor 1 (S1P1), for example, relocalizes upon stimulation to endothelial and immune cell nuclei where it modulates transcription of specific genes in a direct manner. While biological consequences of this novel regulatory mechanism are being uncovered, the mechanisms by which nuclear GPCRs impact gene transcription remain to be elucidated in many cases. We, and others, have shown that Gβγ interacts with and modulates the activity of histone deacetylases and other transcriptional regulators; therefore, we propose that Gβγ plays an important role in the control of transcription by nuclear GPCRs. In support of this hypothesis, our data confirm the presence of a population of Gβγ in the nuclei of normally cycling mammalian cells. We also demonstrate, with microscopy and cellular dissection, that Gβγ enters the nucleus following cell stimulation in a time‐and temperature‐dependence consistent with a co‐translocation with S1P1. The dynamics of Gβγ and its activation by nuclearized S1P1 have a significant impact on Gβγ/HDAC5 complex formation. Clarification of the nuclear entry of Gβγ, its interaction with reversible protein acetylation, and its quantitative impact on transcription will shed new light on the functions of S1P1 and other ubiquitous membrane‐bound receptors.