Endocytosis is the process by which extracellular molecules are captured by the cell surface membrane and then taken up into the cell. Once inside the cell, the internalized material is delivered to its final destination via a complex system of organelles, termed the endosomal network. These heterogeneous structures play a key role in the delivery of extracellular and cellular material towards the lysosome for macromolecular degradation. The internalization of mannose-6-phosphate receptors at the cell surface, and their subsequent delivery to the late endosome, is the basis of enzyme replacement therapy in patients with lysosomal storage diseases (LSDs). This review describes the characteristics of the endosomal network and discusses how disturbances in vesicular trafficking or intracellular signaling may be important in the pathology of LSDs.