Clofarabine is an effective therapy of pediatric patients with relapsed acute lymphoblastic leukemia (ALL). We present a child with Down syndrome who had received previous chemotherapy, cranial radiation, and a stem cell transplant with total body irradiation for her acute lymphoblastic leukemia. She subsequently relapsed and was treated with clofarabine. After her third course, she had a stroke that was felt to be secondary to dehydration and radiation vasculitis. After her subsequent course of clofarabine, she developed fatal neurotoxicity.