TNFRSF25 (DR3) is one of the most recently discovered TNF superfamily receptors and includes an intracellular death domain required to initiate signaling. Over the past decade significant progress has been made in defining the characteristics of this receptor, including the identification of its ligand, TNFSF15 (TL1A). Although TL1A can be provided from a number of sources, signaling through TNFRSF25 is primarily concentrated on T cells. TNFRSF25 signaling can lower the threshold for TCR-induced cell proliferation or cytokine production in an IL-2-dependent manner as well as amplify cytokine production initiated by IL-12 and IL-18. In vivo, TNFRSF25:TL1A signaling has been associated with a number of autoinflammatory conditions including allergic asthma, experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease. Here we discuss the short history of TL1A:TNFRSF25 in health and disease states, including several exciting new observations reported at the 12th international TNF conference, 2009.