Current evidence suggests that T-cell receptor (TCR) recognition of antigen bound to the major histocompatibility complex (Ag-MHC) is insufficient to lead to T-cell proliferation or effector function. For a helper T cell to produce sufficient interleukin 2 (IL-2) to allow autocrine-driven clonal expansion, there is a requirement for so-called 'co-stimulatory' or 'accessory' signals in addition to TCR ligation by Ag-MHC. The interaction of the CD28 receptor on T cells with B7 on antigen-presenting cells (APCs) supplies one such co-stimulatory signal. However, the recent discovery that CD28 and B7 are each members of larger gene families suggests that the regulation of co-stimulation is more complex than previously imagined. Here, Carl June and colleagues highlight recent advances in the understanding of the CD28 and B7 receptor families.