Recognition of self major histocompatability complex (MHC)-presented antigen (MHC:Ag) by the T cell antigen receptor (TCR) is by itself not sufficient to induce T cell proliferation. Rather, to be fully activated T cells require both a TCR-generated signal and a "costimulatory" signal. This important costimulatory signal is not completely understood. Recent evidence suggests that this costimulatory signal is generated by the interaction of the T cell CD28 receptor with the B7 counterreceptor found on antigen-presenting cells. Regulation of costimulation may well prove to be more complex than was previously imagined based on the discovery that CD28 and B7 are each members of larger gene families. The present review highlights recent advances in the understanding of the CD28 and B7 receptor families with an emphasis on controversies in the field. Certain forms of immunopathology that might result from the aberrant regulation of CD28 and/or B7 expression are also discussed.