While rare diseases individually affect a small number of people, they are estimated to collectively affect over 30 million people in the United States. Castleman disease and Rosai-Dorfman-Destombes disease are rare disorders in hematology that can be overlooked despite their significant morbidities. Castleman disease, an atypical lymphoproliferative disorder with a poorly understood pathophysiology, can be particularly challenging with varied presentations. The histology observed on biopsied lymph nodes can be non-specific, requiring careful exclusion of related disorders. Unicentric Castleman disease affects a single lymph node station and is treated by surgical resection where possible. Multicentric Castleman disease (MCD) diagnosis requires not only multiple enlarged lymph node stations but also a systemic inflammatory syndrome with clinical and laboratory manifestations. Half of MCD cases are caused by Kaposi sarcoma herpesvirus infection and best treated with the anti-CD20 monoclonal antibody, rituximab. The other half of cases are idiopathic with the anti-IL-6 (interleukin-6) monoclonal antibody siltuximab as the recommended first-line treatment. Rosai-Dorfman-Destombes disease (RDD) is a non-Langerhans cell histiocytosis with nodal and extra-nodal presentations. In RDD, Mitogen-Activated Protein Kinase (MAPK) pathway mutations have been identified in 30–50% of patients with clinical responses observed with the MAPK Kinase (MEK) inhibitor cobimetinib. Altogether, rare hematologic diseases require careful appreciation of their varied presentations to determine the appropriate therapy. These cases aim to provide the hematologist with a working understanding of how to best diagnose and treat Castleman and Rosai patients.