Mixed-phenotype acute leukemia (MPAL) is a rare disease and comprises 1.5% to 5% of all acute leukemia. The incidence of MPAL was calculated as 0.35/1000000 person-years. A bimodal age distribution was observed with peaks at age 19 and 60 years of age or older. Leukemias with multilineage protein expression often respond poorly to chemotherapy. Two important algorithms have been used to define this entity - EGIL and WHO. In the EGIL and WHO 2001 acute bilineal leukemias were classified as a distinct entity, whereas in the WHO 2008 these are combined with biphenotypic AL as MPAL. The fifth edition of WHO classification of Haematolymphoid Tumours: Myeloid and Histiocytic/ Dendritic Neoplasms has described two new subtypes of ALAL with defining genetic alterations. (i)MPAL with ZNF384 rearrangement (ii) ALAL with BCL11B rearrangement. WHO Haem5 classification further highlights other genomic findings such as PHF6 mutations and PICALM:: MLLT10 fusions During the 1980s, 2 leading hypotheses were raised to explain biphenotypic expression in leukemia - The Greaves hypothesis and “lineage infidelity”. In the current era of targeted therapies, the molecular basis of Mixed phenotypic Acute Leukemia is being studied intensively. HSC/MPPs give rise to cells of the erythroid/megakaryocytic lineage and to myelo-lymphoid precursor cells (MLP). C/EBPs may trans-differentiate erythro/megakaryocytic precursors, T cells and early B cells into inflammatory macrophages. Loss of Pax5 may generate various types of myeloid cells and loss/reduction of Pax5 in B cells may promote neoplastic transformation. Early B cells may be reprogrammed into induced pluripotent stem cells (iPS) by the four ‘Yamanaka transcription factors’ (4YF: Oct4, Sox2, Klf4, c-Myc), whereas late B cells require additional C/EBP for iPS reprogramming.