Transforming growth factor-betas (TGF-βs) are multifunctional cytokines that have been implicated in the regulation of a broad range of biological processes, including cell proliferation, cell survival, and cell differentiation. The three isoforms identified in mammals, TGF-β1, TGF-β2, and TGF-β3, have high sequence homology, bind to the same receptors, and show similar biological functions in many in vitro studies. However, analysis of the in vivo functions of the three isoforms and mice deficient for each cytokine reveals striking differences, illustrating their unique biological importance and functional non-redundancy. Although increasing evidence suggests that TGF-β1 and, to a lesser extent, TGF-β2 play an integral role in maintaining immune tolerance, the immunological role of TGF-β3 has not been carefully evaluated. Recent studies have focused on the multifunctional role of TGF-β3. In this review, we provide an overview of the role of TGF-β3 in immunity, with comparison to TGF-β1 and -β2.