Dendritic cells (DCs) are essential to the induction of pathogen-specific immune responses. The initial interaction between DC and pathogen and the activation of different pattern recognition receptors, such as C-type lectins and Toll-like receptors, dictates the immune response. A prototypic C-type lectin DC-SIGN interacts with a variety of pathogens, including HIV-1, Hepatitis C virus, Mycobacterium tuberculosis and Helicobacter pylori. Although many pathogens interact with this receptor, it is becoming evident that the immunological outcome of this interaction is specific for the pathogen. Recent results suggest that DC-SIGN might cooperate with other innate immune receptors, such as Toll-like receptors to fine-tune the immune responses. Here we will discuss the function of DC-SIGN in the interaction with the myriad of pathogens and its possible cooperation with Toll-like receptors.