Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.