Histiocytic sarcoma (HS) is a rare neoplasm of uncertain etiology. Most recently, the diagnostic criteria for this entity have been revised with inclusion of diagnostic modalities such as immunohistochemical and cytogentic techniques. HS tends to have an aggressive clinical course and presents with systemic symptoms of fever, weight loss, adenopathy, hepatosplenomegly, rash, and pancytopenia. Thalidomide is a promising agent that may exert a therapeutic benefit in HS. We report a case of a 48-year-old female with HS who presented with fever, weight loss, fatigue, generalized anasarca, and pancytopenia. She underwent multi-agent chemotherapy followed by matched unrelated hematopoietic stem cell transplant. Her disease recurred and thalidomide therapy was started, with her overall disease burden significantly reduced as measured radiographically.