Dendritic cells (DCs) tailor adaptive immune responses to specific pathogens. This diversity is mediated by cooperation between different pattern recognition receptors that are triggered by specific pathogens. DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a pattern recognition receptor with a broad pathogen recognition specificity as a result of its affinity for mannose and fucose carbohydrates. DC-SIGN induces very diverse immune responses to different pathogens, such as bacteria, fungi, helminths and viruses. Recent data show that DC-SIGN triggering by pathogens modulates Toll-like receptor signaling at the level of nuclear factor-kappaB. In this article, we will discuss the signaling pathways induced by DC-SIGN and its central role in the regulation of adaptive immunity to bacterial, fungal and viral pathogens.