TNFRSF21 (death receptor-6, DR6) is an orphan TNF receptor superfamily member and belongs to a subgroup of receptors called death receptors. DR6 is expressed ubiquitously with high expression in lymphoid organs, heart, brain and pancreas. Ectopic expression of DR6 in some cell lines leads to apoptosis and activation of the JNK and NF-κB pathways. Some tumor cells overexpress DR6, typically in conjunction with elevated anti-apoptosis molecules. DR6 deficient mice (DR6−/−) show normal development with no gross pathology in any major organs. In the absence of DR6, ligation of the TCR results in enhanced T-cell proliferation, activation and skewed Th2 cytokine production. Similarly, B-cells lacking Dr6 show increased proliferation, cell division and cell survival upon mitogenic stimulation (anti-CD40 and LPS) or BCR ligation. As a result, DR6−/− mice show increased Th2 immune responses to both T-dependent and -independent antigens. All those data indicate that DR6 plays an important regulatory role for the generation of adaptive immunity. More importantly, DR6−/− mice are resistant to EAE and allergic airway hypersensitivity, possibly as a result of a deficiency in the migration of antigen specific T-cells. Therefore, DR6 is a potential therapeutic target for treating inflammatory and autoimmune disease by means of biological intervention. In addition, DR6 is highly expressed in many tumor cell lines and tumor samples. Interestingly, both of its transcriptional and cell surface expression are regulated by the NF-κB pathway and metalloproteinase in some tumor cell lines, respectively. The role of DR6 as an apoptosis-inducing receptor is less clear and perhaps cell type dependent. Therefore, in addition to its roles in regulating immune responses, DR6 may also be involved in tumor cell survival and immune evasion, which is subject to future investigations.