Many human cancers metastasize to lymph nodes via invasion of lymphatic vessels close to the primary tumor. Although the capacity for nodal metastasis is a well recognized property of tumor cells themselves, it is also possible that the process is enhanced by properties specific to tumor lymphatics, acquired during growth within the tumor environment. The authors have tested this hypothesis by comparing the transcriptional and immunohistochemical profile of primary lymphatic endothelial cells (LECs) isolated by LYVE-1 immunomagnetic bead selection from highly metastatic T-241/VEGF-C murine fibrosarcomas and normal murine dermal lymphatic vessels. The cover figure illustrates the authentic LYVE-1/CD31/VEGFR-3/podoplanin/Prox1+ve phenotype of both normal and fibrosarcoma LECs assessed by fluorescence microscopy and flow cytometry and the 792 transcripts that display more than twofold up-/down-regulation between the two populations assessed by Affymetrix microarray analysis. The data identify a number of new tumor LEC markers of potential prognostic significance for human cancers. In addition, they reveal an intriguing up-regulation of the endothelial tight junction adhesion molecule ESAM in tumor lymphatics that correlates closely with nodal metastasis in both human head and neck and colorectal carcinomas. For details, see the article by Clasper and colleagues on page 7293 of this issue.