The author’s laboratory studies interactions between human T lymphocytes and vascular endothelial cells (EC). Our work is organized around three hypotheses. First, we propose that vascular EC can initiate secondary (i.e., recall) immune reactions by presenting antigenic peptide-major histocompatibility complex (MHC) complexes to those circulating memory T cells whose cognate antigen is locally present within a peripheral tissue, e.g., as a consequence of infection or allogeneic transplantation. In this way, EC can increase the efficiency of immune surveillance. Second, we propose that T cell signals, both secreted (e.g., cytokines) and contact-dependent (e.g., CD40 ligand), activate new gene expression in EC that induce the capacity to perform new effector functions, such as leukocyte recruitment and activation or initiation of intravascular coagulation. In this way, EC can particpate as effector cells for cell-mediated immune reactions. Third, we propose that EC are major targets of immune-mediated injury. Consequently, increasing resistance of endothelium to immune effector mechanisms may protect tissues from damage, e.g., in allograft rejection. These three hypotheses are explored through in vitro experiments, through analyses of human tissue specimens, and through in vivo studies employing novel human-mouse chimeric animals.