This article presents the most recent insights into the biology, prognostic significance, and therapeutic approaches to TEL/AML1-positive leukemia. The TEL/AML1 fusion gene, also known as ETV6 /CBFA2, is the most commonly occurring gene rearrangement in pediatric acute lymphoblastic leukemia (ALL). Considerable controversy exists over its prognostic significance with currently available therapies. Differences in outcome may be explained by the differing intensities of various chemotherapy regimens, individual host responses to chemotherapy, or the hypothesis that relapsed TEL/AML1-positive leukemia represents an outgrowth of a secondary leukemia that shares a common initiating event with the first. Incorporating knowledge of this gene rearrangement into treatment decisions serves as a paradigm for translating molecular discoveries into clinically meaningful data to direct patient care and improve outcome.