The mannose receptor (MR) is an endocytic and phagocytic receptor belonging to the C-type lectin superfamily. A number of functions have been ascribed to this receptor, which is involved in innate and adaptive immune responses. The MR binds carbohydrate moieties on several pathogens, such as bacteria, fungi, parasites, and viruses, and, therefore, is considered a pattern recognition receptor (PRR). In addition, MR binds endogenous molecules and was originally described as a membrane-associated component binding lysosomal glycosidases in alveolar macrophages. Since its identification more than 25 years ago, many other endogenous ligands were described, including hormones, enzymes, cell membranes, extracellular matrix components, and normal as well as tumoral mucins. The MR is preferentially expressed on immune cells of myeloid lineage, especially subsets of dendritic cells (DC) and tissue macrophages. In addition to immune cells, specialized endothelial cells are also MR-positive. Increasing evidence shows that the MR is involved in the silent clearance of inflammatory molecules. In this review, we discuss current knowledge about the receptor and show that endogenous ligands activate an anti-inflammatory and tolerogenic program in DC and macrophages, thus reinforcing the hypothesis that the MR has an important role in the maintenance of homeostasis.