A marked improvement in the outcome of patients with acute lymphoblastic leukemia has been achieved with chemotherapeutic agents developed between the 1950s and 1970s. As the limits of optimizing the use of old drugs are reached, most adults with acute lymphoblastic leukemia still succumb to their disease and leukemia remains the leading cause of nonaccidental death in children. Salvage regimens, based mostly on different combinations of the same agents used in front-line therapy, carry a high incidence of morbidity and dismal long-term survival rates. New therapeutic strategies are needed. Clofarabine, a next-generation deoxyadenosine analog, has demonstrated significant activity in children and adults with refractory lymphoid and myeloid leukemia in early clinical trials and was granted approval for use in children with acute lymphoblastic leukemia in second or higher relapse. This is the only anticancer drug to receive primary indication for use in children over the past decade. Ongoing studies are exploring the benefit of clofarabine combinations in less heavily pretreated patients and the use of different dose schedules in a variety of hematological malignancies.