Nearly half of the proteins linked to demyelinating subtypes of Charcot-Marie-Tooth disease regulate endo-lysosomal trafficking. Most of these proteins are expressed in all human tissues, yet defects caused by loss-of-function mutations are largely isolated to the peripheral nervous system. This observation suggests that myelinating Schwann cells are particularly vulnerable to endosomal trafficking defects, yet the molecular mechanisms that orchestrate this cell-specific vulnerability remain unclear. We hypothesize that endosomal trafficking provides the specific control needed to regulate pro-myelination signals and coordinate cytoskeletal rearrangements during axon sorting and myelination. All cells require the trafficking of membrane receptors, but the work described within this dissertation suggests that Schwann cells rely heavily on endo-lysosomal membrane trafficking for all aspects of their biology. Highlighting why changes in phosphoinositide hydrolysis and endosomal trafficking cause peripheral neuropathy.