FGD5 (FYVE, RhoGEF and PH domain containing 5) is a guanine nucleotide exchange factor that activates CDC42, a Rho family GTPase, by catalyzing GDP-GTP exchange. This activation mediates VEGF-induced signaling in vascular endothelial cells, regulating proangiogenic processes including angiogenesis, cell migration, and proliferation through actin cytoskeleton reorganization. At the tissue level, FGD5 plays critical roles in epithelial-stromal crosstalk. In mammary glands, FGD5 expressed in basal cells inhibits ATF3 transcriptional activity, promoting CXCL14 secretion 1. This CXCL14/CXCR4/ERK signaling in endothelial cells activates hedgehog ligands, establishing a positive feedback loop supporting basal cell expansion and ductal morphogenesis 1. FGD5 also serves as a marker identifying functional hematopoietic stem cells in expansion cultures, linked with expression signatures of proliferating fetal HSCs 2. Clinically, FGD5 genetic variants (rs2342882, rs35850039) are significantly associated with increased risk of death or heart failure rehospitalization in multiethnic cohorts 3, suggesting involvement in cardiovascular homeostasis. The FGD5 locus shows multiple disease associations via genome-wide studies, though the precise mechanisms require further investigation. The related lncRNA FGD5-AS1 functions independently in cancer progression and myocardial injury, highlighting complex regulatory networks at this genomic locus.