The transmembrane CD83 molecule, a conserved member of the immunoglobulin superfamily, is known as one of the most characteristic cell surface markers for fully matured dendritic cells (DCs) in the peripheral circulation. An essential role for CD83 on murine DCs has not been found; however, evidence shows that its function primarily lies in the regulation of T- and B-lymphocyte maturation and in the regulation of their peripheral responses. Here, we review evidence for a role of CD83 in central lymphocyte maturation and novel, sometimes contradictory findings, regarding the function of CD83 in peripheral immune responses.