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.