HVEM (Herpes virus entry mediator), also known as TNFRSF14, is a member of the tumor necrosis factor (TNF) receptor family that mediates herpes virus entry into cells during infection. Upon overexpression, HVEM activates NF-κB and AP-1 through a TNF receptor-associated factor (TRAF)-mediated mechanism. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-α, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, tumor progression and resistance to immune response. It has been demonstrated that HVEM induces a novel signaling pathway downstream leading to signal transduction and activation of STAT3 in epithelial cells. Since STAT3 regulates the expression of genes important for host defense in epithelial cells, as well as the differentiation of retinoid-related orphan receptor RORγt+, Th17, and innate lymphoid cells. This finding suggests that HVEM may play an important role in mucosal host defense.