Both clofarabine and nelarabine recently received an accelerated approval by the US Food and Drug Administration for use in refractory or relapsed pediatric acute lymphoblastic leukemia and in refractory-relapsed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Both drugs have been studied for their metabolism and mechanisms of action in preclinical investigations and for their efficacy in clinical trials. This review will summarize these investigations and will suggest future plans with these nucleoside analogs. Clofarabine and nelarabine were designed based on preclinical and clinical findings with other nucleoside analogs or normal deoxynucleotides such as dGTP. Studies in cell lines have demonstrated that triphosphate is the active metabolite for both these purine nucleoside analogs. Pharmacokinetic and pharmacodynamic investigations during clinical trials have verified the importance of triphosphate levels in achieving clinical responses. Several phase I and II clinical explorations have suggested the utility of clofarabine in acute leukemias and nelarabine in T-cell diseases. Dose-limiting toxicities were nonhematologic: hepatotoxicity for clofarabine and neurotoxicity for nelarabine. Clofarabine is the first deoxyadenosine analog that shows promise in adult and pediatric acute leukemias without untoward toxicity. Nelarabine, as expected from its design, is a drug that may be directed to T-cell diseases.