Cytosine arabinoside (AraC) is one of the most active drugs in the treatment of acute leukemias and is widely applied at all phases of therapy. In spite of extensive clinical and experimental investigations, its intracellular metabolism and especially its mechanism of action are still not fully elucidated. Controversy also continues about the most appropriate way and dose of administration; which differs by more than 100 fold in clinical studies ranging from low-dose, over standard and intermediate dose regimens, to high-dose protocols. The present review is focused on the role and place of high-dose AraC treatment in acute myeloid leukemia (AML). Based on available clinical and experimental data, the following conclusions can be drawn: Not considering possible but not yet demonstrated beneficial long-term effects, the incorporation of high-dose AraC into induction therapy has not resulted in an improvement of overall remission rate, with the possible exception of patients with slow initial cytoreduction after a first course of conventional treatment. Promising results, however, emerge from high-dose AraC-based consolidation protocols, which need confirmation in prospectively randomized comparative trials. In relapsed and refractory AML, higher than conventional doses undoubtedly enhance the efficacy of AraC salvage therapy. The question of whether the antileukemic activity of intermediate-dose regimens with 500-1,000 mg/m2 AraC is equivalent to that of high-dose protocols applying 2,000-3,000 mg/m2 AraC, however, remains open but may soon be answered by ongoing controlled clinical and pharmacologic investigations.