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. Several recent studies have shown that activation of GPCRs can impact on -catenin signaling. -catenin is the main effecter of the Wnt signaling 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 -catenin, activation of TCF-dependent transcription and up-regulation of Wnt target genes, c-Jun, Fra-1 and c-Myc. These results are observed in HEK293/GnRH receptor expressing cells and have been recapitulated in LT2 and T3–1 mouse gonadotrope cells. In addition to these findings, we show that GnRH treatment mediates the inactivation of Glycogen Synthase Kinase-3 (GSK-3), a protein serine/threonine kinase that regulates -catenin degradation within the Wnt signaling pathway. Our findings extend the number of GPCRs that can target -catenin signaling through diverse pathways. Furthermore, this is the first demonstration of the targeting of Wnt/-catenin signaling by a peptide hormone GPCR.