Aggressive histiocytic lesions are uncommon in the pediatric population. These neoplasms occur in isolation or after therapy for other types of hematopoietic malignancy such as T-cell acute lymphoblastic leukemia. The etiology of these lesions is poorly understood, and no definitive standard of care has been established for patients with these diagnoses. Here, we report the success of thalidomide treatment for 2 subtypes of histiocytic proliferation—metastatic histiocytic sarcoma and extracutaneous juvenile xanthogranuloma—in pediatric patients. Our findings highlight the importance of considering thalidomide therapy in this unique and difficult to treat patient population.