The crucial role for CD28, its homolog CTLA-4 and their binding partners B7-1 and B7-2 in the generation of effective T-cell responses has been well documented. Recently, two new pairs of the CD28/B7 families were identified. The ability of these molecules to regulate T-cell expansion and effector function and the dynamic integration of the co-stimulatory and T-cell receptor signals are just beginning to be explored. Understanding these processes will be crucial for designing clinically relevant approaches to manipulate the adaptive immune system.