B and T lymphocyte associated (BTLA) is an Ig domain superfamily protein with cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Its ligand, herpesvirus entry mediator (HVEM), is a tumor necrosis factor receptor superfamily member. The unique interaction between BTLA and HVEM allows for a system of bidirectional signaling that must be appropriately regulated to balance the outcome of the immune response. HVEM engagement of BTLA produces inhibitory signals through SH2 domain–containing protein tyrosine phosphatase 1 (Shp-1) and Shp-2 association, whereas BTLA engagement of HVEM produces proinflammatory signals via activation of NF-κB. The BTLA-HVEM interaction is intriguing and quite complex given that HVEM has four other ligands that also influence immune responses, the conventional TNF ligand LIGHT and lymphotoxin α, as well as herpes simplex virus glycoprotein D and the glycosylphosphatidylinositol-linked Ig domain protein CD160. BTLA-HVEM interactions have been shown to regulate responses in several pathogen and autoimmune settings, but our understanding of this complex system of interactions is certainly incomplete. Recent findings of spontaneous inflammation in BTLA-deficient mice may provide an important clue.