VGLL1 is an X-linked transcriptional coactivator that functions as a specific cofactor for TEAD transcription factors (TEAD1-4) through a conserved valine-x-x-histidine-phenylalanine domain 1. It operates in the nucleus to regulate transcription by RNA polymerase II through histone acetylation and chrX accessibility modulation 2. In normal physiology, VGLL1 is highly expressed almost exclusively in placental trophoblasts, where it cooperates with TEAD4, GATA3, and TFAP2C to control human trophectoderm lineage specification and trophoblast stem cell self-renewal 2. However, VGLL1 acts as an onco-placental protein aberrantly expressed in multiple aggressive human malignancies 3. In cancer, TGF-β signaling promotes VGLL1 phosphorylation at serine 84 via the ERK/RSK2 pathway, enhancing VGLL1-TEAD4 binding and transcriptional activation of pro-tumorigenic genes including MMP9 and EGFR 45. VGLL1 upregulation drives resistance to estrogen receptor-targeted therapies in breast cancer and is associated with poor prognosis across multiple cancer types 56. Notably, VGLL1 alterations also define a new class of benign intraparenchymal CNS schwannomas 7. Pharmacological disruption of VGLL1-TEAD interactions represents a promising therapeutic strategy for treating resistant cancers.