The process of lymphoid maturation is tightly controlled by the hierarchical activation of transcription factors and selection through functional signal transduction. Acute lymphoblastic leukemia (ALL) represents a group of B/T-precursor-stage lymphoid cell malignancies arising from genetic alterations that block lymphoid differentiation and drive aberrant cell proliferation and survival. With recent advances in next-generation sequencing, we are discovering new mutations affecting normal lymphopoiesis and the significance of cooperating mutations, as well as epigenetic alterations. The data obtained in this way aids in the evaluation of prognosis in the individual patient but, importantly, also in incorporating targeted therapy appropriate for the mutational abnormality.