T-cell malignancies have distinct biochemical, immunologic, and clinical features which set them apart from non-T-cell malignancies. In the past, T-cell leukemia portended a worse prognosis than leukemia of B-cell origin. Cure rates have improved with intensification of therapy and advanced understanding of the molecular genetics of T-cell malignancies. Further advances in the treatment of T-cell leukemia will require the development of novel agents that can target specific malignancies without a significant increase in toxicity. Nelarabine (2-amino-9β-D-arabinosyl-6-methoxy-9H-guanine), a synthesized guanosine nucleoside prodrug of ara-G (9-β-D-arabinofuranosylguanine), recently received accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory T-ALL and T-LBL in adults and children. Nelarabine is water soluble and rapidly converted to ara-G, which is specifically cytotoxic to T-lymphocytes and T-lymphoblastoid cells. Clinical and pharmacokinetic investigations have established that nelarabine is active as a single agent which has led to exploration of an expanded role in the treatment of T-cell hematologic malignances.