Researchers have identified five receptors thai bind to the death ligand Apo2L TRAIL, of which four are cell-associated. These four receptors contain closely related extracellular cysteine-rich domains, and belong to the TNFR genesuperfamily: their encoding human genes map to chromosome 8p21 -22. DR4 and DR5 have a cytoplasmic death domain that signals apoptosis. DcRl is a GPI-linked protein that lacks a cytoplasmic region. DcR2 has a cytoplasmic tail that contains a truncated, nonfunctional death domain. Upon overexpression. DcRl and DcR2 inhibit apop-tosis induction by Apo2L TRAIL, indicating that they can act as decoys that compete for ligand binding to DR4and DR5. Whereas many tumor cell lines express DR4 and/or DR5. few express significant levels of DcR 1 or DcR2. Activation of T cells suppresses DcR1 expression completely, which is consistent with the implication of Apo2L TRAIL in activation-induced apoptosis of T cells. Activation of p53 in some tumor cell lines induces DR5 and DcRl mRNA expression, which suggests a possible connection between p53 and receptors for Apo2L.TRAIL. Apo2L.TRAIL induces apoptosis in a wide variety of cancer cell lines by engaging DR4 and DR5. but it is not cytotoxic towards most normal cell types studied so far. Thus, it may be possible to treat cancer effectively by targeting tumor DR4 and DR5 with Apo2L,TRAIL, without significant toxicity to normal tissues.