Children with Down syndrome (DS) have an increased risk for developing both acute myeloid as well as acute lymphoblastic leukemia. These leukemias differ in clinical characteristics and biology compared to leukemias in non-DS children. Moreover, children with DS have an increased risk of side-effects from cytostatic therapy, which complicates their treatment. Myeloid leukemia in children with DS (ML-DS) is a unique disease entity. ML-DS blasts are relatively sensitive to chemotherapy, which enables dose- reductions. This also leads to a decrease in toxicity;together resulting in improved outcome compared to AML in non-DS children. Therefore, a European treatment protocol specifically for ML- DS was recently implemented. ML-DS is often preceded by a pre- leukemic clone in newborns (transient leukemia: TL), which in most cases resolves spontaneously. However, in case of severe symptoms treatment is indicated. Twenty percent of TL patients subsequentiy develop myeloid leukemia. To improve treatment and survival of children with TL, and to study if transition to ML-DS can be prevented by early treatment in the TL phase, a nation-wide TL surveillance and treatment protocol has been opened in the Netherlands recendy. The prognosis of DS-ALL patients is at best similar to non-DS-ALL patients. The biological characteristics of leukemic lymphoblasts differ between DS-ALL and non-DS-ALL. DS-ALL lymphoblasts do not have increased sensitivity to chemotherapy compared to non-DS lymphoblasts. Therefore dose-reduction should only be considered in case of unacceptable toxicity. Recent findings suggest that DS-ALL patients experience excessive toxicity during the current DCOG ALLio-protocol. Hence, adjustments in the treatment protocol for DS-ALL patients were made.