The essentials of the mechanism that targets soluble proteins to lysosomes were described more than a decade ago t, Soluble lysosomal hydrolases are tagged with mannose 6-phosphate (M6P) in the Golgl complex and transported by specific mannose. 6-phosphate receptors (M6PRs) to late endosomes en route to lysosomes. However, the mechanisms that target membrane proteins to lysosomes are only now being deciphered. tnformation about the sorting motifs that target membrane proteins to endosomes has come mostly from studying resident lysosomal proteins, proteins targeted to lysosomes for disposal, and M6PRs. These studies are revealing that membrane proteins use a variety of tyrosine, and leucine. based sorting motifs (YXXZ/NXXY and LZ, where Z indicates one of the hydrophobic amino acids: L,!, V, M, C or A) in their cytoplasmic tails to select ti~ e TGN ox the plasma membrane as the points of entry into the endosomal corridor to lysosomes (Fig. 1).