Castleman disease was initially described over 50 years ago as a benign localized mass of lymph nodes found primarily in the mediastinum of asymptomatic patients. Subsequently, additional types were recognized that extend the spectrum of this heterogeneous group of diseases. Optimal standard therapies have not been established. Currently, most patients receive treatments derived from past experience with non-Hodgkin lymphoma that are not altogether satisfactory.Advances in understanding the biological basis of Castleman disease have provided new targets for therapeutic exploitation. Recognition of the role of interleukin-6 in disease perpetuation has led to the use of an antihuman interleukin-6 receptor monoclonal antibody, tocilizumab. Rituximab, an anti-CD20 monoclonal antibody, targets CD20-positive B lymphocytes, a prominent component of this disorder. Human herpes virus-8 and angiogenesis, both involved in the pathogenesis of Castleman disease, may provide additional unique therapeutic opportunities.Rational approaches to the treatment of Castleman disease have begun to have an impact on disease management; however, the role of these new agents remains to be established. As the complexity of Castleman disease is more fully understood, additional targets for new innovative therapies undoubtedly will be identified.