The protein composition of the integral lysosomal membrane and the membrane-associated compartment have been defined in part by proteomics approaches. While the role of its constituent hydrolases in a large array of human disorders has been well-documented, the manner in which membrane proteins are integrated into the organelle, the multiprotein complexes that form at the organelle's cytosolic surface and their roles in the biogenesis and functional control of the organelle are now emerging. Defining cytosolic targeting complexes that affect the function of the lysosomal/endosomal compartment may help to identify the lysosome's role in a variety of human pathologies.