Lysosomal hydrolases have long been known to be responsible for the degradation 
of different substrates in the cell. These acid hydrolases are synthesized in 
the rough endoplasmic reticulum and transported through the Golgi apparatus to 
the trans-Golgi network (TGN). From there, they are delivered to 
endosomal/lysosomal compartments, where they finally become active due to the 
acidic pH characteristic of the lysosomal compartment. The majority of the 
enzymes leave the TGN after modification with mannose-6-phosphate (M6P) 
residues, which are specifically recognized by M6P receptors (MPRs), ensuring 
their transport to the endosomal/lysosomal system. Although M6P receptors play a 
major role in the intracellular transport of newly synthesized lysosomal enzymes 
in mammalian cells, several lines of evidence suggest the existence of 
alternative processes of lysosomal targeting. Among them, the two that are 
mediated by the M6P alternative receptors, lysosomal integral membrane protein 
(LIMP-2) and sortilin, have gained unequivocal support. LIMP-2 was shown to be 
implicated in the delivery of beta-glucocerebrosidase (GCase) to the lysosomes, 
whereas sortilin has been suggested to be a multifunctional receptor capable of 
binding several different ligands, including neurotensin and receptor-associated 
protein (RAP), and of targeting several proteins to the lysosome, including 
sphingolipid activator proteins (prosaposin and GM2 activator protein), acid 
sphingomyelinase and cathepsins D and H. Here, we review the current knowledge 
on these two proteins: their discovery, study, structural features and cellular 
function, with special attention to their role as alternative receptors to 
lysosomal trafficking. Recent studies associating both LIMP2 and sortilin to 
disease are also extensively reviewed.