While adult acute lymphoblastic leukemia (ALL) is curable in 40–50% of the patients, the individual prognosis is rather unpredictable due to associated biological and clinical risk factors. In both B- and T-precursor ALL, minimal residual disease (MRD) represents the most sensitive prognostic marker, useful to support critical treatment decisions, ranging from allogeneic stem cell transplantation in patients with inadequate MRD response to chemotherapy only in MRD responsive ones. This optimized risk-adapted strategy allows to spare transplant-associated morbidity and mortality in patients curable by chemotherapy. Further progress is expected from the integration of the MRD-based strategy with improved pediatric-type regimens and novel targeting agents for discrete ALL subsets. These changes are increasing the cure rate to above 50%.