Autoimmune diseases occur when the immune response is targeted to self-antigens, leading to destruction or altered function of specific cells and tissues. Although the aetiology of these diseases has not yet been fully elucidated, it is believed that genetically determined susceptibility and environmental triggers are both implicated in the detrimental immune response against the body's own tissues. Dendritic cells (DCs) are professional antigen presenting cells that play an important role in maintaining peripheral tolerance by preventing self-reactive T cells from causing autoimmune damage. Thus, alterations in the physiology of DCs are likely to be responsible for defective immune regulatory mechanisms and incomplete tolerance to self. Here, we will focus specifically on the ways in which the immunological synapse occurring at the DC-T cell interface can fine-tune the balance between tolerance and immunity and how alterations of this synapse can determine induction or perpetuation of autoimmune responses. Activating/inhibitory receptors expressed on the surface of DCs and T cells modulate the function of these cells and influence the course of the immune response. Pharmacological approaches that can modulate DC function will be also addressed as a potential antigen-specific strategy in the design of new, noninvasive therapies to prevent or to treat chronic inflammatory autoimmune disorders.