Dendritic cells (DCs) are highly susceptible to extrinsic signals that modify the functions of these crucial APCs. Maturation of DCs induced by diverse proinflammatory conditions promotes immune responses, but certain signals also induce tolerogenic functions in DCs. These “induced tolerogenic DCs” help to moderate immune responses such as those to commensals present at specific anatomical locations. However, also under steady-state conditions, some DCs are characterized by inherent tolerogenic properties. The immunomodulatory mechanisms constitutively present in such “natural tolerogenic DCs” help to promote tolerance to peripheral Ags. By extending tolerance initially established in the thymus, these functions of DCs help to regulate autoimmune and other immune responses. In this review we will discuss the mechanisms and functions of natural and induced tolerogenic DCs and offer further insight into how their possible manipulations may ultimately lead to more precise treatments for various immune-mediated conditions and diseases.