Tumor necrosis factor super family 15 (TNFSF15) is one of the more recently identified TNF ligands. Emerging studies are beginning to reveal the function of TNFSF15 in physiology and pathology. TNFSF15 has been found to have a prominent role in endothelial cell biology. The abundance of TNFSF15 in the vasculature suggests that the endothelium be the major production site of this cytokine. TNFSF15 has been shown to be a negative regulator of angiogenesis with a unique characteristic of inhibiting proliferation only on endothelial cells. In addition, TNFSF15 is also involved in the modulation of inflammation. It stimulates T cell activation, Th1 cytokine production, and dendritic cell maturation. Thus, similar to other TNF ligands, TNFSF15 is a multifunctional, yet specialized, cytokine. The various functions of TNFSF15 are mostly mediated by death receptor 3 (DR3). We review the experimental evidences on the identification, isoforms, structure and expression of TNFSF15, and its activities in anti-angiogenesis, anti-tumor, inflammation and immune system mobilization.