Abstract: The avoidance of autoimmunity requires mechanisms to actively silence or tolerize self reactive T cells in the periphery. During infection, dendritic cells are not only capturing microbial antigens, but also are processing self antigens from dying cells as well as innocuous environmental proteins. Since the dendritic cells are maturing in response to microbial and other stimuli, peptides will be presented from both noxious and innocuous antigens. Therefore it would be valuable to have mechanisms whereby dendritic cells, prior to infection, establish tolerance to those self and environmental antigens that can be processed upon pathogen encounter. In the steady state, prior to acute infection and inflammation, dendritic cells are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. These immature cells are not inactive, however. They continuously circulate through tissues and into lymphoid organs, capturing self antigens as well as innocuous environmental proteins. Recent experiments have provided direct evidence that antigen‐loaded immature dendritic in vivo silence T cells either by deleting them or by expanding regulatory T cells. In this way, it is proposed that the immune system overcomes at least some of the risk of developing autoimmunity and chronic inflammation. It is proposed that dendritic cells play a major role in defining immunologic self, not only centrally in the thymus but also in the periphery.