Signal transduction through CD28 plays an important role in regulating the initial response of a T cell to antigen. Two distinct CD28 ligands, B7-1 (CD80) and B7-2 (CD86), have been identified. These ligands also bind to CTLA-4, a receptor closely related to CD28 that is expressed on activated T cells. Recent studies designed to examine the individual roles of B7-1 and B7-2 in the regulation of an in vivo immune response have demonstrated that costimulation through CD28, CTLA-4, or both is more complex than previously believed. In vivo, the costimulatory ligands B7-1 and B7-2 appear to differ in their ability to potentiate the differentiation of T helper (Th) cells into either type 1 (Thl) cells, which direct cell-mediated immunity, or type 2 (Th2) cells, which support a humoral immune response. These results have important implications for our understanding of in vivo immune responses as well as for strategies of immunotherapy involving the CD28 costimuiatory pathway.