Acute leukemia is a heterogeneous group of disorders, characterized by different laboratory and prognostic features. An adequate diagnosis of acute leukemia, based on the identification of a leukemic cell population and the hematopoietic lineage assessment, is the first goal toward defining correct risk stratification of patients and tailoring specific therapies to patients. Diagnosis of acute leukemia underwent an important change since the 1970s when the only available diagnostic tools were cytomorphology and cytochemistry. Nowadays, the development of modern techniques and their combined use in a multimodal approach lead to a better identification and sub‐classification of acute leukemia. Thus, blast identification in acute leukemia required a comprehensive global approach, by combining cytomorphology, cytochemistry, multiparameter flow cytometry (MFC), cytogenetic, fluorescence in situ hybridization (FISH) and molecular genetic methods. At least, new sequencing technologies, such as gene expression profiling (GEP) and whole‐genome sequencing, DNA methylation arrays, and comparative genomic hybridization array, could represent the new frontiers in the characterization of genetic heterogeneity in acute leukemia. WIREs Data Mining Knowl Discov 2015, 5:74–85. doi: 10.1002/widm.1146 Conflict of interest: The authors have declared no conflicts of interest for this article. This article is categorized under: Application Areas > Health Care