DCs are a complex cell population in the skin consisting of epidermal LCs and dermal DCs, which differ in their anatomic location, antigen recognition, processing machinery, and migratory capacity. Cutaneous DCs (LCs as well as dermal DCs) function as sentinels that survey invading agents and transmit the information into immune responses by taking up exogenous antigens, migrating to draining LNs, and presenting the processed antigens to T cells resulting in T-cell differentiation and activation. Indeed, further studies are needed to clarify the specific contribution of each cutaneous DC subpopulation to antigen presentation and induction of cutaneous immune responses. Recent results suggested to revisit the "paradigm" that exclusively immigrant LCs present skin-acquired antigens to T cells upon reaching the draining LNs, because viral antigens, for instance, are presented by a DC subpopulation other than LCs after infection of mouse epidermis with herpes simplex virus [153]. Additionally, different DC subpopulations may sequentially present skin-acquired antigens, possibly serving as a regulatory mechanism of cell-mediated immunity and adding further complexity to established concepts. Nevertheless, cutaneous DCs are involved in several pathologies (including infections, inflammatory disorders, or skin cancers) and play a pivotal role in regulating the balance between immunity and peripheral tolerance. However, it is widely accepted that (cutaneous) DC in an immature state may have tolerogenic properties resulting in the induction or expansion of Tregs. CD4+CD25+ Tregs are essential for the control of immune responses in inflammatory, autoimmune, or cancer diseases, and it is well established that in particular the lineage-specific transcription factor Foxp3, as well as cytokines (including IL-2, IL-10, and TGF-beta), characteristic surface markers such as CTLA-4, and members of the TNF superfamily (e.g., RANKL) are critically involved in the thymic development, peripheral maintenance, and suppressive activity of CD4+CD25+ Tregs. Recently, new methods for generating and expanding Tregs in vitro have emerged and supported the use of CD4+CD25+ T cells as a novel strategy for the treatment of patients suffering from autoimmune diseases. In the future, a better understanding of Treg function in vivo and the interactions of Tregs and pathogenic effector T cells in autoimmune disorders may help to improve the design of Treg-based therapies.