Receptors and their ligands on T cells and antigen-presenting cells are crucial for delivering inhibitory or stimulatory signals that enable immune cells to remain dormant or to respond effectively to various stimuli. The CD28–B7 and tumor necrosis factor receptor (TNFR)–TNF superfamilies contain many of these molecules and were thought to be distinct functioning modules. However, two studies have now provided a new perspective in this already complex area, showing not only a crosstalk between these superfamilies but potentially between co-stimulatory and co-inhibitory receptors.