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The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self‐directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self‐cells that largely display the same array of surface molecules as the cells from which …