Blood vessels facilitate the widespread dissemination of cancer cells in metastasis. Interactions between circulating intravascular cancer cells and the microvasculature involve mechanical contact and transient attachment, mediated by endothelial surface adhesion molecules and their ligands on the neoplastic cells. Initial interactions trigger a sequence of activation pathways that involve cytokines, growth factors, bioactive lipids, and reactive oxygen species produced by the cancer cell or the endothelium. These activation steps elicit the expression of integrin adhesion molecules in cancer cells and the endothelium, matrix metalloproteinases, and chemotactic factors that promote firm attachment of tumor cells to the vessel wall and transvascular penetration. On the other hand, induction of endothelial free radicals can be cytotoxic to cancer cells. Collectively, the sum of these interactions act as a rate-regulating step in the metastatic process.