Lysosomes are composed of soluble and transmembrane proteins that are targeted to lysosomes in a signal-dependent manner. The majority of soluble acid hydrolases are modified with mannose 6-phosphate (M6P) residues, allowing their recognition by M6P receptors in the Golgi complex and ensuing transport to the endosomal/lysosomal system. Other soluble enzymes and non-enzymatic proteins are transported to lysosomes in an M6P-independent manner mediated by alternative receptors such as the lysosomal integral membrane protein LIMP-2 or sortilin. Sorting of cargo receptors and lysosomal transmembrane proteins requires sorting signals present in their cytosolic domains. These signals include dileucine-based motifs, DXXLL or [DE]XXXL[LI], and tyrosine-based motifs, YXXØ, which interact with components of clathrin coats such as GGAs or adaptor protein complexes. In addition, phosphorylation and lipid modifications regulate signal recognition and trafficking of lysosomal membrane proteins. The complex interaction of both luminal and cytosolic signals with recognition proteins guarantees the specific and directed transport of proteins to lysosomes.