In the present review, the authors described the pathobiological features of B- and T-ALL, which appear to be quite heterogeneous with regard to molecular pathogenesis. The last edition of the World Health Organization Classification considered this aspect by defining many entities based on genetic findings. This approach is not only important for prognostic stratification, but also in the near future will surely represent the basis for the definition of patient-specific therapeutic approaches. A striking example is Ph+ acute lymphoblastic leukemia (ALL), which until the advent of tyrosine kinase inhibitors (TKI) has been regarded as the most aggressive ALL. The use of imatinib, dasatinib, and possibly more recent inhibitors has dramatically changed the clinical scenario, offering new opportunities to patients, especially the elderly. Similarly, the use of FLT3 inhibitors in mixed lineage leukemia-positive cases, gamma-secretase inhibitors in T-ALL, novel TKI, and monoclonal antibodies may represent a successful approach in the future.