Abstract: Castleman disease (CD) is a rare polyclonal lymphoproliferative disorder characterized by enlarged hyperplastic lymph node(s). Unicentric Castleman disease (UCD) is an indolent condition often treated by local approaches. On the contrary, patients with multicentric Castleman disease (MCD) have less favorable prognoses and require systemic treatments. Cytotoxic chemotherapy has been widely used to treat MCD with varying degrees of response because of the toxicity risk of the treatment. The pathogenesis remains unknown; however, most pieces of evidence to date point toward human herpes virus 8 (HHV-8) and deregulated overproduction of interleukin (IL-6). Discovery of putative etiologic factors and targets in MCD, particularly HHV-8, CD20, and IL-6, has translated to the use of rituximab, anti-IL-6-based, and antiviral therapy. Good results have been realized through targeting HHV-8 replication, CD20, and IL-6 pathways. In this article, we reviewed the classification, pathogenesis, and current treatments of CD and provided insights into future treatment strategies based on disease biology.