Lysosomes are intracellular membrane-bound organelles that perform the final degradation of many cellular macromolecules. This is achieved by the action of a number of lysosomal enzymes (originally called “acid hydrolases” because of the low internal pH characteristic of lysosomes). These enzymes are synthesized in the endoplasmic reticulum (ER) on membrane-bound ribosomes and traverse the ER-Golgi pathway along with other newly synthesized proteins. At the terminal Golgi compartment (the trans-Golgi network or TGN), they are segregated from all other glycoproteins and selectively delivered to lysosomes. In most “higher” animal cells, this specialized trafficking is achieved primarily by a specific glycan marker that is recognized by certain receptors. This chapter describes the discovery and characterization of this glycan-mediated biological system, which relies on recognition of glycans containing mannose-6-phosphate (M6P) by “P-type” lectins. This was the first clear-cut example of a biological role for glycans on mammalian glycoproteins and the first demonstrated link between glycoprotein biosynthesis and human disease. The interesting history of its discovery is therefore described in some detail.