The composite phenotype of a population of leukemic blast cells is derived through analysis of morphology, cytochemistry, cytogenetics, surface antigens, and gene structure. When analyzed in such a fashion, approximately 10-25% of childhood acute leukemias will show markers of more than one lineage; these may be coexpressed on individual cells (biphenotypic) or appear on two distinct blast populations (bilineal or biclonal). Occasionally, there is conversion from one leukemic phenotype at diagnosis to another phenotype at relapse (lineage shift). Mixed lineage features appear to have biologic and prognostic significance. Some specific mixed lineage leukemia syndromes have been identified; among them are acute nonlymphoid leukemia with T-lymphoid features, CD7+, CD4-, CD8- acute leukemia, CD2+/CD19+ acute lymphoid leukemia, and acute leukemias associated with specific cytogenetic markers, e.g., t(4;11) and t(9;22). In general, these forms of acute leukemia along with others with mixed lineage markers have a poor prognosis, and new therapeutic approaches appear to be indicated.