--- - |2+ Abstract Acute lymphoblastic leukemia (ALL), one of the most common malignant human disorders, originates in different important genetic lesions in T‐cell or B‐cell progenitors. ALL is a malignant lymphoid progenitor with peak prevalence in children (2–5 years). The rate of survival when one is suffering from ALL depends on various agents including the age of the patient, responses to anti‐leukemic therapy, and cell biology. miRNAs and epigenetics are important regulatory factors in the expression of genes. miRNAs are noncoding RNA with inhibitory effectors on specific mRNA. Patterns of DNA methylation are profoundly changed in ALL by epigenetic mechanisms. The deciphering of miRNA and the epigenetic pathogenesis in ALL could revolutionize response to the therapy and outcome, and create an enormous promise for novel approaches to reduce the toxic side‐effects of intensive leukemia. Hence, pathogenetic miRNAs and epigenetics leading to the initiation and the progression of ALL are summarized in this review. This article is protected by copyright. All rights reserved - Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-.