Acute leukemias of ambiguous lineage may be divided into acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemias (MPALs). AULs are leukemias with very primitive phenotypes that lack definitive lineage-specific antigens. MPAL encompasses rare blastic hematopoietic cell neoplasms that express a mixture of myeloid and lymphoid (B- or T-lineage) antigens. The 2008 World Health Organization (WHO) classification defines several categories of MPALs based on the presence of recurrent cytogenetic lesions or in their absence, on the lineage of the leukemic blasts, defined as B-myeloid, T-myeloid, B-T, or B-T-myeloid. Any of these leukemias can develop as biphenotypic or bilineal (bilineage) acute leukemias. The WHO 2016 update will maintain WHO 2008 criteria for MPAL with additional clarifications. This chapter summarizes the clinical and pathologic features of this rare leukemic subentity.