Molecular mechanisms regulating transforming growth factor-beta (TGF-beta) induction of Foxp3 (forkhead box P3) expression and thus induction of induced regulatory T cells (Tregs) have been the focus of a great deal of study in recent years. It has become clear that this process is influenced by a number of factors as perhaps might be predicted by the fact that there is an overarching need of the immune system to finetune response to environmental antigens. In this review we discuss these mechanisms, with the aim of presenting a broad picture of how the various observations fit together to form an integrated regulatory regime.