Although it is possible to introduce enzymes and other proteins into lysosomes by nonspecific or "fluid" endocytosis, this process is very inefficient. Efficiency and selectivity are provided by the interaction of receptors on the cell surface and specific markers on the protein. Because most lysosomal enzymes are glycoproteins, the carbohydrate recognition systems are particularly relevant to their uptake. The systems that have been discovered are cell-specific and recognize the following terminal sugar residues: mammalian hepatocytes, galactose (also N-acetylgalactosamine, glucose) and L-fucose; avian hepatocytes, N-acetylglucosamine; mammalian reticuloendothelial cells, mannose (also N-acetylglucosamine, glucose); human fibroblasts, mannose 6-phosphate. Because of the ubiquity of mannose-terminated oligosaccharide chains on lysosomal enzymes derived from tissues, the reticuloendothelial system is probably of major importance in clearing injected enzymes from the circulation. The mannose 6-phosphate recognition system probably functions in directing endogenous enzymes, synthesized by fibroblasts, to the lysosomes of these cells. The existence of cell-specific recognition systems presents a challenge to future attempts at enzyme replacement in lysosomal storage diseases; enzymes will have to be selected or modified to have the appropriate marker for uptake by the cells where storage occurs.