140 exome/transcriptome NGS approaches, novel and recurring lesions have been identified in B and T-ALL. The identifi- cation of these alterations allowed a better classification of leukemia patients in subgroups according to specific genetic lesions (eg, BCR-ABL1 like subgroup), provided new markers for risk-assessment and/or for monitoring minimal residual disease (eg, IKZF1, CRLF2, TP53), and highlighted novel therapeutic approaches (eg, inhibitors of JAK2, HDAC, and NOTCH1). However, much remains to be in- vestigated. From the biological prospective, whole exome/ transcriptome NGS approaches will provide a comprehen- sive view of the complexity of genetic alterations in ALL, identifying genes and pathways relevant for the establish- ment of the leukemia clone and/or for the disease recurrence and responsible for responsiveness to therapy. 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