Human acute leukemias (AL) are classified as myeloid or lymphoid according to cytomorphology and the expression of leukocyte differentiation antigens/CD-markers. However, in the minority of cases leukemic cells express markers of more than one lineage, which has led to the introduction of a new subgroup of acute leukemias termed mixed or biphenotypic acute leukemias (BAL). In an effort to distinguish between BAL and those AL with aberrant expression of markers of other lineage, the European Group for the Immunological Characterization of Acute Leukemias (EGIL) has proposed a scoring system in which CD-markers are assigned a score of 0.5, 1.0 or 2.0, depending on the specificity of a particular antigen for myeloid, B- and/or T-lymphoid lineage, respectively. The new WHO classification of hematologic tumors has adopted the EGIL criteria for BAL and introduced a new group of AL termed 'AL of ambiguous lineage'. In addition to BAL in which a single cell population expresses both myeloid and lymphoid differentiation markers, this new group of leukemias also comprises cases that present with two separate blast populations (acute bilineal leukemia, aBLL). In general, BAL accounts for less than 5% of all AL cases, whereas aBLL is a rare disease constituting 1%-2% of AL cases that contains B- or T-lymphoid along with myeloid blasts. Chromosome abnormalities are frequent in both entities with a relatively high incidence of Philadelphia chromosome and rearrangements involving 11q23, especially in cases with B- and myeloid involvement. Other biological features include CD34 expression and multi-drug resistance P-glycoprotein overexpression. The prognosis of BAL and aBLL is unfavorable, with poor prognostic factors being age, high WBC and the presence of Philadelphia chromosome. Unfortunately, optimal therapy is not known, although regimens designed for acute lymphoblastic leukemia may result in a better response rate. Collaborative studies are needed for better understanding of the biology of these entities and establishment of standard therapeutic protocols.