Clofarabine is a good generation purine nucleoside analogue designed to overcome the limitations and to incorporate the best qualities of both cladribine and fludarabine. Clofarabine is thought to work via three mechanisms: inhibition of ribonucleotide reductase; incorporation to DNA; and induction of apoptosis. Given these mechanism of action, clofarabine would be predicted to act synergistically with other chemotherapeutic agents such as other purine nucleoside analogues and DNA damaging or cross linking agents such as anthracyclines and platinum-based compounds. Intravenous clofarabine showed significant efficacy in pediatric leukemias (specifically, acute lymphoblastic leukemia (ALL)) and, in 2004, it was approved by the United States Food and Drug Administration (FDA) for the treatment of pediatric relapsed/refractory ALL after at least two regimens. In adults, clofarabine has shown significant efficacy in hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) alone and in combinations. Ongoing and future studies will examine the use of clofarabine in elderly patients with AML for whom standard regimens are too toxic, and in MDS intravenous and oral forms of the drug.