Angiogenesis is essential for normal development of the placenta. Aberrant angiogenesis within the placental terminal villi results in structural and vascular abnormalities including altered endothelial cell function, ultimately compromising maternal-fetal exchange in placental pathologies such as fetal growth restriction (FGR). In the placenta, angiogenesis is controlled by transcription factors. Homeobox genes are a family of transcription factors that regulate vascular development in embryonic and adult tissues, but their role in the microvasculature of the placenta is unknown. Initial screening for homeobox genes in the freshly isolated placental endothelial cells revealed the presence of known placental homeobox genes such as HLX1, DLX3, DLX4, MSX2 and GAX1. Subsequent microarray expression profiling revealed the presence of novel homeobox genes HEX, TGIF, LHX6, MEIS2E2. HEX expression was predominantly localized to the microvascular endothelial cells of human term placenta, is increased in FGR-affected placentae compared with gestation-matched controls. HEX is a regulator of angiogenesis in macrovascular endothelial cells, where it targets a number of angiogenesis-related genes3. The functional role of HEX was determined using three independent siRNAs. Following HEX inactivation, proliferation, network formation and migration of placental endothelial cells were significantly decreased compared to non-specific siRNA control. Down-stream target genes of HEX were identified following gene inactivation for HEX in placental endothelial cells using TaqMan Signature arrays specific for endothelial cell biology and angiogenesis (Applied Biossytems). Potential downstream target genes of HEX were identified as cytokines IL11, CXCL5; extracellular matrix proteins collagen IV, MMP2 and MMP9; angiogenic proteins including Ang1, Endoglin1,FGF, FLT1 and neuroplin and apoptotic marker CASP6. Further validation of targets of HEX showed differential expression in FGR-affected placentae compared to control. These studies suggest that the altered expression of homeobox genes may contribute to the abnormal vascular development associated with FGR.