C-type lectins play important roles in both innate and adaptive immune responses. In contrast to the mannose- or fucose-specific C-type lectins DC-SIGN and mannose receptor, the galactose-type lectins, of which only macrophage galactose-type lectin (MGL) is found within the immune system, are less well known. MGL is selectively expressed by immature dendritic cells and macrophages with elevated levels on tolerogenic or alternatively activated subsets. Human MGL has an exclusive specificity for rare terminal GalNAc structures, which are revealed on the tumor-associated mucin MUC1 and CD45 on effector T cells. These findings implicate MGL in the homeostatic control of adaptive immunity. We discuss here the functional similarities and differences between MGL orthologs and compare MGL to its closest homolog, the liver-specific asialoglycoprotein receptor (ASGP-R).