4-1BB was originally described as a cDNA expressed by activated murine T cells and subsequently demonstrated to encode a member of the tumor necrosis factor receptor family of integral membrane proteins. Recently, a murine ligand for 4-1BB (mu4-1BB-L) was cloned and demonstrated to be a member of an emerging family of ligands with structural homology to tumor necrosis factor. Both monoclonal antibody to hu4-1BB and cells transfected with hu4-1BB-L induced a strong proliferative response in mitogen co-stimulated primary T cells. In contrast, ligation of 4-1BB on T cell clones enhanced activation-induced cell death when triggered by engagement of the TCR/CD3 complex. To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. It has been shown that primary human T cells expressing CD80 and 4-1BBL vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice.