Langerhans cell histiocytosis (LCH) and Ewing sarcoma represent lesions of unknown histogenesis. Both lesions typically affect children and adolescents. Imaging features frequently suggest the diagnosis, and both lesions may demonstrate aggressive characteristics. LCH shows a broader spectrum of imaging findings, depending on lesion activity and location, which are reviewed in this article. Ewing sarcoma typically reveals both osseous and soft tissue involvement, although direct continuity of the components is often not apparent. Knowledge of the spectrum of clinical and radiologic features facilitates early diagnosis and can be used to evaluate the effects of therapy.