The development of resistance to Ara-C by leukemia cells may be a multifactorial process. These include diminished rates of anabolism or increased rate of catabolism to Ara-C, competition for incorporation into DNA by higher pool size of the competing normal metabolite, dCTP and perhaps other mechanisms. Laboratory investigations have shown that cellular resistance to lower doses of Ara-C (LoDAC) may be overcome by a substantial increase in the extracellular concentration (dose-effect). Clinical extrapolation of these observations have shown that high dose Ara-C (HiDAC) is effective in re-inducing remission in patients with acute leukemia who have either failed to enter remission or who relapsed while being treated with LoDAC. Other laboratory investigations indicate significant schedule-dependent synergy between sequential HiDAC and asparaginase. Application of these observations to clinical trial has resulted in a 64% complete remission rate in patients with non-lymphocytic leukemia, including those who were previously treated with LoDAC or who had had an antecedent hematologic disorder. Toxicity from this regimen was not significantly different from those employing LoDAC. These preliminary data in patients with high risk disease would suggest that HiDAC/asparaginase might have significant utility in patients with previously untreated acute non-lymphocytic leukemia.