The C-type lectins are a superfamily of proteins that recognize a broad repertoire of ligands and that regulate a diverse range of physiological functions. Most research attention has focused on the ability of C-type lectins to function in innate and adaptive antimicrobial immune responses, but these proteins are increasingly being recognized to have a major role in autoimmune diseases and to contribute to many other aspects of multicellular existence. Defects in these molecules lead to developmental and physiological abnormalities, as well as altered susceptibility to infectious and non-infectious diseases. In this Review, we present an overview of the roles of C-type lectins in immunity and homeostasis, with an emphasis on the most exciting recent discoveries.