Dendritic cell (DC) migration to draining lymph nodes is crucial for adaptive immune responses and is driven by various chemokine receptors and adhesion molecules. This study identifies another molecular interaction involved in this process, showing that the expression of C-type lectin receptor 2 (CLEC2) by DCs promotes their migration along podoplanin (PDPN)-expressing stroma. PDPN is highly expressed by lymphatic endothelial cells and fibroblastic reticular cells; engagement of CLEC2 by PDPN led to cytoskeletal rearrangements in migrating DCs that allowed them to spread and migrate along these stromal surfaces. DCs that lacked CLEC2 expression had an impaired ability to migrate to draining lymph nodes and initiate adaptive T cell responses.