Tissue-resident dendritic cells (DCs) that migrate from peripheral sites to lymphoid organs are essential in the initiation of adaptive immune responses and for the maintenance of peripheral tolerance, and have been extensively studied. By contrast, blood-borne DCs represent a heterogeneous population, the origin, destination and function of which are still unclear. Recent studies have shown that circulating DCs capture blood-borne antigen and transport it into the extra-vascular space of lymphoid tissues for processing and presentation. Other findings suggest that a fraction of tissue-resident DCs might enter the blood after having acquired antigen in the periphery. Together, these studies imply that circulating DCs might modulate immune responses by translocating antigenic material from its point of origin to remote target tissues.