Considerable confusion exists regarding the definition of acute mixed-lineage leukemia. We have proposed a list of strict criteria, limiting the term acute mixed-lineage leukemia to those patients whose blast cells co-express lymphoid and myeloid characteristics. This system includes cytochemical, immunologic, molecular, and cytogenetic characteristics that are strongly associated with either lymphoid or myeloid lineages. As more information becomes available, the criteria for mixed-lineage leukemia will undoubtedly change. Identification of patients with mixed-lineage leukemia and metachronous leukemia (lineage switch) is important for determining the prognostic implications of these findings. Care must be taken in identifying cases of metachronous leukemia because of the increased incidence of second malignancies following aggressive therapy. Evidence of a recurrence of the original clone must be obtained before metachronous leukemia can be diagnosed. As with mixed-lineage and metachronous leukemias, the potential clinical and prognostic implications of lymphoid leukemias with antigenic asynchrony should be identified. The asynchronous antigen expression in leukemic lymphoblasts may provide a means for detecting minimal residual disease. Detection of minimal residual leukemia is possible because these blasts differ from the predominant population of normal lymphoid cells in their expression of cell surface markers. Study of the mechanisms that lead to these unusual leukemias may result in better understanding of the processes that underlie both normal hematopoietic differentiation and leukemogenesis. An understanding of these leukemias may also permit identification of cases that are destined to fail current therapies so that more intensive or selective therapy can be instituted for such children. Curing the 30% of children with ALL that relapse despite our best efforts should be one of the top priorities for pediatric oncologists.