Acute lymphoblastic leukaemia in children with Down syndrome (ALL-DS) is characterised by unique clinical and biological features. Notable among these are an absence of ALL in DS patients <1 year of age; a lower incidence of favourable and unfavourable chromosomal translocations; heightened sensitivity to methotrexate; and an increased propensity to infections. Although children with ALL-DS have historically fared less well than their non-DS counterparts (ALL-NDS), recent data indicate that outcomes in ALL-DS are now comparable with ALL-NDS with risk-adapted therapies, after adjusting for biological differences between the ALL-DS and ALL-NDS populations. Given the increased risk of ALL-DS patients for treatment-related toxicities, further intensification of therapy may not yield continued improvements in survival. Future investigations in the ALL-DS population should focus on maintaining excellent outcomes while reducing treatment-related complications through novel treatment strategies, such as the integration of targeted noncytotoxic agents.