Attenuating coinhibitory molecules for the treatment of cancer is gaining a great deal of attention as a strategy for immunotherapy. The B and T lymphocyte attenuator (BTLA, CD272) is a novel coinhibitory molecule structurally and functionally related to CTLA-4 and PD-1. A study in this issue of the JCI by Derré et al. reveals that BTLA is expressed on virus-specific human CD8+ T cells but is progressively downregulated after their differentiation from a naive to effector phenotype (see the related article beginning on page 157). Surprisingly, tumor-specific human CD8+ T cells continue to express BTLA even after their differentiation to an effector phenotype. Remarkably, vaccination of melanoma patients with CpG led to BTLA downregulation on tumor-specific human CD8+ T cells, concomitant with restoration of their functionality. We discuss these findings in the context of the expanding field of cosignaling molecules and their implications for T cell-based therapies for cancer.