The gonadotropin-releasing hormone (GnRH) receptor is a G-protein-coupled receptor (GPCR), and its ligand GnRH is the central regulator of the reproductive system. GnRH receptors are known to target a wide variety of signal transduction pathways. These include classical Gq / Gs / Gi heterotrimeric G-protein signalling, and activation of the small G-protein Rac1 to promote cytoskeletal reorganization. Several recent studies have shown that activation of GPCRs can impact on β-catenin signalling. β-catenin is the main effector of the Wnt pathway where it acts with the transcription factors TCF/LEF to mediate the transcription of Wnt target genes. We show that GnRH treatment promotes the nuclear accumulation of β-catenin, activation of β-catenin/TCF-dependent transcription and up-regulation of Wnt target genes, c-Jun, Fra-1 and c-Myc. These results are observed in HEK 293/GnRH receptor expressing cells and have been recapitulated using LβT2 and αT3-1 mouse gonadotrope cells. A normal consequence of Wnt signalling is the inhibition of Glycogen Synthase Kinase (GSK-3), allowing the accumulation of β-catenin. Our data shows a time-dependent inhibition of GSK-3 in response to GnRH treatment. Various chemical inhibitors and dominant-negative mutant constructs were employed to elucidate the signal transduction pathway mediating these events. Our findings extend the number of GPCRs that can target β-catenin signalling through diverse pathways. Furthermore, this is the first demonstration of the regulation of β-catenin/TCF-dependent transcription by a peptide hormone GPCR.