The mannose-6-phosphate (Man-6P)/IGF-II receptor is a multifunctional receptor which binds with a high affinity on distinct sites two strikingly different classes of ligands: IGF-II, and Man-6P bearing molecules such as lysosomal enzymes or other biologically relevant ligands (TGF beta precursor, EGF receptor, proliferin...). Binding of each ligand on its cognate site is severely decreased in the presence of the other type of ligand, thus revealing that the two distinct sites are strongly interacting (steric hindrance, conformational change). Any imbalance in ligands and receptor concentration in various pathological situations (transformation, tumor, altered hormonal levels...) is thus likely to perturb their associated biological functions in the targeting and routing of lysosomal enzymes or Man-6P ligands or in the autocrine/paracrine IGF-II--induced cellular responses.