Langerhans cell histiocytosis (LCH) is the most common type of histiocytosis. LCH is now recognized as an “inflammatory myeloid neoplasia”, which combines features of “hematological malignancy” and “inflammation”. Although the prognosis for LCH is good, LCH often develops various permanent consequences (PCs) resulting from the disease. LCH-associated neurodegenerative disease (LCH-ND) is the most serious PC in patients with LCH. The pathophysiology of LCH-ND, which was not well understood for many years, has come to be more significantly understood with advances in molecular biological techniques, and promising treatments have come into sight. Here, we review the current understanding of the pathogenesis and treatment of LCH-ND. After that, challenges for preventing it are discussed.