Dendritic cells (DCs) are the ubiquitous sentinels of the immune system, instructing and shaping the adaptive immune response. As such, DCs are often targeted directly by pathogens as a means of immune evasion. Although DCs in different anatomical locations originate from common bone-marrow-derived progenitors and, hence, share several characteristics, microenvironmental factors have an important influence on DC biology under both steady-state and inflammatory conditions. A growing body of literature suggests that these instructive processes are mediated by tissue stromal cells, empowering these cells with a decisive role in local immune regulation. Here, we review recent progress in this area, focussing on the role of stromal cells in supporting the generation of regulatory DCs, and propose that tissue stromal cells provide an alternate avenue whereby pathogens can influence DC function.