The t(4;11)(q21;q23) has been associated with marked lineage heterogeneity. Most of the reported cases were classified as acute lymphoblastic leukemia (ALL). The t(4;11) is one of the commonest specific chromosomal translocations in ALL, occurring in 2% of childhood and 5% of adult cases. In childhood ALL, this translocation is associated with female sex, age less than 1 year, hyperleukocytosis, CD10-/CD19+ B-precursor cell immunophenotype, and myeloid-associated antigen (CD15) expression. There also appears to be an age-related difference in treatment outcome. Adults had the worst prognosis, and children aged 1 to 9 years appeared to have a better outcome than infants or adolescents. Reported cases of acute myeloid leukemia (AML) or secondary leukemia with the t(4;11) have not been well characterized. It is intriguing that virtually all of the reported cases with secondary leukemia had received epipodophyllotoxins or doxorubicin, agents that affect topoisomerase II and are associated with secondary AML characterized by 11q23 abnormalities. Identification of the involved gene(s) in the t(4;11) will provide a molecular approach permitting more accurate classification of these cases.