Tumor endothelial marker 8 (TEM8) is a recently described protein preferentially expressed in the tumor vasculature of multiple human malignancies. TEM8 is believed to have roles in tumor angiogenesis as it influences endothelial cell adhesion and migration, and its expression levels correlate with the extent of tumor involvement. To evaluate the efficacy of targeting TEM8, Fernando and Fletcher created a gene encoding a fusion protein that specifically binds TEM8 and delivers truncated tissue factor as a vascular disrupting agent. Using the Sleeping Beauty transposon system to systemically deliver the gene encoding the fusion protein, they showed gene expression within the lung and the ability of the fusion protein to accumulate within the tumor vasculature. Gene delivery led to delayed tumor growth, disruption of the tumor vasculature, and localized areas of tumor necrosis. The cover image illustrates the presence of TEM8 (green) in tumor vessels that colocalizes with endothelial cells (red); however, the data suggests that not all TEM8-positive cells are of endothelial origin. For details, see the article by Fernando and Fletcher on page 5126 of this issue.