Proper cell homeostasis requires the efficient transport of a large variety of soluble acid hydrolases and transmembrane proteins from the trans-Golgi network (TGN) to lysosomes. While most of these molecules reach this degradative compartment, some transmembrane proteins, in particular, the acid hydrolase receptors are retrieved to the TGN. This bidirectional transport process involves the formation of several vesicular transport intermediates in which cargo molecules are selectively packaged. This review summarizes our current understanding of the molecular mechanisms leading to the proper targeting of lysosomal proteins.