Recurrence of childhood acute lymphoblastic leukemia occurs in about 30-50% and indicates irresistable progression of the disease. While systemic (= hematologic) relapse is due to drug resistance of leukemic cells, pharmacologic barriers may be responsible for local relapses as meningeal involvement, leukemic ophthalmopathy or testicular infiltration. L-asparginase seems to be an important component of drug combinations for re-induction therapy for systemic relapse. Following reinduction therapy modification of continuation therapy is necessary. Local relapses require local treatment, i.e. radiotherapy and e.g. intrathecal drug application. Local relapse is almost always followed by hematologic relapse. Therefore, intensification of systemic therapy is also recommended. Prevention of these relapses is much more important and probably more successful than treatment. Therefore, initial therapy should include preventive measures for pharmacologic sanctuaries.