The immune system, a highly effective and dynamic cellular network, protects a host from pathogens. Therefore, the immune system must distinguish self from nonself structures, but also between harmful and innocuous foreign Ags to prevent nonessential and self-destructive immune responses. The induction of Ag-specific T cell tolerance and its maintenance in the periphery are critical to prevent autoaggressive immune responses. A still growing body of evidence reveals that specific T cell populations that have suppressive/regulatory properties tightly control autoaggressive immune responses. Among the CD4+ regulatory T cells (Tregs) 3 basically two different subsets of Tregs can be differentiated by their distinct suppressive mechanisms. Naturally occurring CD4+ CD25+ Tregs exert their suppressive effects obviously via cell contact by membrane-bound molecules although the nature of these molecules is still elusive. The suppressive capacity of the second subset, Th3 and type 1 T regulatory (Tr1) cells, is contact independent and is based mainly on cytokines such as IL-10 and TGF-β. It seems that these cells, in contrast to naturally occurring CD4+ CD25+ Tregs, represent altered states of differentiation rather than a unique cell lineage. However, the interrelationship of these distinct subsets of CD4+ Tregs is currently a matter of debate.