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The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 (<i>NPM1-mut</i>) is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. <i>NPM1-mut</i> AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, <i>NPM1-mut</i> AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, <i>NPM1-mut</i> is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of <i>NPM1-mut</i> AML patients.