Clofarabine is a second-generation purine nucleoside analog and has significant anti-leukemic activity as a single agent. It is approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children. Combinations of clofarabine with purine nucleoside analogs or DNA-damaging agents have been investigated utilizing synergistic effects and now tested in a number of studies including a frontline study. In this article, we review the development of clofarabine, rationale and history of combination regimens, and their potential roles and toxicities in the treatment of pediatric ALL that are important to treating clinicians. Pediatr Blood Cancer 2012;59:417-422. (c) 2012 Wiley Periodicals, Inc.