C-type lectins belong to a superfamily of receptors that share structural homology in their carbohydrate recognition domains and often bind to carbohydrates in a Ca-dependent fashion. Whereas endocytic C-type lectin receptors (CLRs) trigger the receptor-mediated endocytosis of soluble ligands, myeloid CLRs in innate immunity act as pattern recognition receptors and contribute to the initiation of immune responses. Thus, CLR targeting may serve as a means to mediate cellspecific drug/gene delivery but also to modulate immune responses. In this chapter, CLR targeting is described using the examples of the asialoglycoprotein receptor (ASGPR) and the DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). Furthermore, a protocol is given that specifies the generation of CLR-Fc fusion proteins. CLR-Fc fusion proteins consist of the extracellular part of the respective CLR and the Fc fragment of IgG molecules. They are helpful tools to identify novel CLR ligands on pathogens or in libraries of synthetic glycan structures. The identified CLR ligands can then be covalently attached to model antigens to analyze their utility for antigen-presenting cell targeting to modulate immune responses.