Langerhans cell histiocytosis (LCH) is a rare clonal disorder that consists of single or multiple mass lesions composed of cells with an abnormal Langerhans cell phenotype. Its etiology remains unknown, despite extensive searches for evidence of consistent cytogenetic abnormalities, gene rearrangements, or viral genomes. Similarly, the pathogenesis of the disease is enigmatic, although the altered expression of cytokines and cellular adhesion molecules, important for migration and homing of the activated normal Langerhans cell, may play an important role. The biologic behavior of LCH ranges from spontaneous remission to lethal dissemination, and such behavior cannot be predicted on the basis of histologic features. The presence and degree of organ dysfunction, together with the patient's age at diagnosis, remain the most reliable indicators of prognosis. Treatment of severe, refractory disease continues to be controversial and, in many cases, ineffectual. The revised classification scheme for LCH and related disorders recognizes the uncertain biological potential of LCH and its relation to other processes of dendritic and macrophage origin.