Abstract: Tumor necrosis factor receptor-associated death domain protein（TRADD） is initially identified as an intracellular adaptor molecule for signaling nuclear factor-κB（NF-κB） and apoptostic pathways mediated by tumor necrosis factor receptor 1（TNFR1）. TRADD consists of two functional domains, the N-terminal TNF receptor associated factor（TRAF） binding domain and the C-terminal death domain（DD）. The TRADD-DD can recruit a variety of downstream DD-containing proteins through homotypic DD interactions, resulting in propagation of different signals and thus various functional events, such as apoptosis, inflammatory signal transduction and so on. In addition, TRADD signaling is also implicated in the occurrence and progression of many human diseases. This review mainly introduces the research progress on TRADD-mediated signal pathways, especially the NF-κB pathway, the structural basis of TRADD signaling, and a series of TRADD-related diseases.