Recent research into the genetic basis and the molecular disease mechanisms of Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathies, has highlighted phosphoinositides, membrane-tethered phosphorylated metabolites of phosphatidylinositol, as key regulatory molecules in peripheral nerves in health and disease. Enzymes that dephosphorylate the endosomal phosphoinositides phosphatidylinositol-3-phosphate and/or phosphatidylinositol-3,5-biphosphate, and proteins with binding domains for these phosphoinositides, are mutated in subtypes of CMT. A hypothetical picture emerges suggesting that the precise regulation of phosphoinositide levels within neural cells, a process in turn critical for the correct dynamics of proteins binding to phosphoinositides, is a crucial bottleneck for the accurate function of myelinated peripheral nerves in both neurons and Schwann cells. The underlying molecular and cellular mechanisms are largely unknown. Some hypotheses are discussed in this essay.