The term histiocytosis identifies a group of disorders characterized by localized or generalized reactive or neoplastic proliferation of cells similar, if not identical, to cells of the mononuclear phagocyte and dendritic cell systems. In Langerhans cell histiocytosis (LCH), the proliferating cell is the Langerhans cell, and the morphologic and immunohistochemical criteria for the definitive diagnosis of LCH have been established. The clinically evident pathology of LCH is broadly divided into two categories: direct involvement with the disease (e.g., lytic lesions of the bone or organ involvement) and secondary consequences resulting from permanent damage by the primary disease, LCH (eg, diabetes insipidus, fractures, and tooth loss). Current knowledge suggests tailoring the therapy to the extent of disease. Single-system disease can be treated by excisional biopsy, low-dose radiotherapy, or mild chemotherapy. Multisystem disease should be treated with combination chemotherapy, and current experimental therapeutic approaches include randomized treatment protocols for multisystem disease. A pressing current controversy regarding LCH is that its etiology is unknown. Whether LCH is reactive or neoplastic is even debated, and several features provide seemingly contradictory evidence on this point (spontaneous resolution of disease on one hand and clonality of lesional LCH cells on the other), underscoring the need for further studies to elucidate the etiology and pathogenesis of LCH.