Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similarities in that abnormal proliferations of lymphocytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, and Castleman's disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expression or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chromosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the "inflammatory response" camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don't have a "malignant" morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collaborations of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome. In Section II, Dr. Yasodha Natkunam reviews the features of SHML, which most often presents as painless cervical lymphadenopathy, although many patients can have extranodal involvement as well. These sites include the skin, respiratory tract, bone, lung, gastrointestinal tract, and brain. The diagnosis rests on finding intact lymphocytes in the cytoplasm of activated macrophages as well as accumulation of mature plasma cells. Hemolytic or non-hemolytic anemias, hypergammaglobulinemia, and elevated erythrocyte sedimentatin rate (ESR) are often found with SHML. An intriguing finding of human herpesvirus (HHV)-6 viral proteins in SHML has been reported in several patients, but needs further study. SHML associated with lymphoproliferations triggered by defects in apoptosis are discussed since this mechanism may provide a clue to the etiology. Therapy for SHML varies greatly in reported case series. Many patients have spontaneous regression or resolution after surgical removal of isolated node groups. Others with systemic involvement may benefit from chemotherapy, but no clinical trials have been done. In Section III, Dr. Steven Swerdlow clarifies key features of the four types of CD. Localized cases are divided into the hyaline vascular type and plasma cell type. Both are usually cured by surgical excision and have symptoms mainly of a mass lesion, although the latter often also has constitutional symptoms. The two types are distinguished largely by the nature of the follicles and the number of interfollicular plasma cells. Interleukin (IL)-6 expression is increased in the plasma cell type. Multicentric CD of the plasmablastic type is most often found in HIV-positive patients with coincident HHV-8 infection. Many have lymphomas or Kaposi sarcomas. Other cases of multicentric CD are also most like the plasma cell type, however, with disseminated disease and constitutional symptoms. A wide variety of anti-neoplastic drugs, radiation therapy, anti-IL-6 and rituximab or atlizumab have been used with varying success in patients with multicentric CD. Clinical trials are needed for SHML and CD and registration of adult and pediatric patients on current LCH trials are encouraged.