The Ets transcription factors regulate a wide variety of biologic processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1 is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression is also enriched in tumor blood vessels, and have identified a short peptide, 34 amino acids in length, corresponding to the terminal portion of the highly conserved ETS domain that potently blocks the function of ELF-1. A tailored ELF-1 blocking peptide, containing a 12-amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets including Tie2 and endothelial nitric oxide synthase. Furthermore, the ELF-1 blocking peptide potently inhibits angiopoietin-1-mediated endothelial cell migration. Systemic administration of this peptide markedly attenuates B16 melanoma tumor growth and tumor-associated angiogenesis in nude mice. These results support the function of ELF-1 in the regulation of Tie2 gene expression during the development of tumor angiogenesis.