The tumor necrosis factor (TNF)-related cytokines have emerged over the past 2 years as a large family of pleiotropic mediators of host defense and immune regulation. Members of this family exist in membrane-anchored forms acting locally through cell-to-cell contact, or as secreted proteins capable diffusion to more distant targets. A parallel family of receptors signals the presence of these molecules leading to the initiation of cell death or cellular proliferation and differentiation in the target tissue (see Smith et al. 1994; Banchereau et al. 1994 for reviews). The focus of this review is on two members of this family produced by activated T cells, the original lymphotoxin-α (LT-α, previously referred to as TNF-β), and a new member, lymphotoxin-β (LT-β), and their specific receptors. Initially discovered by cytotoxic activity in vitro, lymphotoxn, as a secreted molecule, was one of the earliest postulated mechanisms used by cytotoxic T lymphocytes (Ruddle and Waksman 1968; Granger and Williams 1868). The molecular cloning of LT and TNF dramatically revised the view of these cytokines as limited nonspecific cytotoxins and revealed their more intricate role in immunoregulation and host defense. Although once thought to be merely a redundant form of TNF, new findings have indicated that lymphotoxin has a role in immune physiology distinct from TNF and forms a system of secreted and membrane-anchored immunoregulatory molecules.