Previous work has shown that optimal activation of CD4+ T cells requires co-stimulatory signals in addition to the primary signal provided by the antigen receptor. Recent work has demonstrated that CD28 is the primary co-stimulatory signal receptor for T cells, and B7 its natural ligand on antigen presenting cells. In the past year, it has become clear that the importance of CD28-mediated co-stimulatory signals extends to virtually all T-cell subsets. In addition, the existence of multiple ligands that are differentially expressed on antigen-presenting cells has been documented. The picture that is emerging is of a complex and dynamic interplay of co-stimulatory molecules on both the T cell and the antigen-presenting cell that serves to regulate activation. This offers novel approaches to the manipulation of immune responses in vivo.