B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed by lymphoid cells that negatively regulates the immune response. Consistent with an inhibitory role of BTLA, the lupus disease is exacerbated in BTLA-deficient lupus mice, suggesting a protective role for BTLA in lupus. This obviously opened the door to the development of new therapeutic approaches targeting the BTLA pathway to treat autoimmune disorders. Some agonist anti-BTLA antibodies have been recently developed and their efficacy in various immune-mediated diseases including lupus, is currently under evaluation. However, we and others, evidenced defective BTLA expression and/or function in B and T cells from lupus patients. Given that the inhibitory function of BTLA is critically regulated by its surface expression and signal transduction, altered BTLA expression in lupus cell subsets may limit efficient BTLA targeting. Expanding our understanding of BTLA biology will bring important clues for the design of new BTLA-targeting therapeutic strategies.