&NA;The effectiveness of antileukemic therapy is limited by intrinsic and acquired cellular resistance. Preclinical investigations support a complex and redundant network of cytoprotective mechanisms resulting from decreased drug accumulation, intracellular drug detoxification, alterations in nuclear targets of the antineoplastic agent, impaired transduction of growth arrest signals, and inherent cytokinetic resistance to S‐phase active agents. Some, but not all, of these mechanisms are coordinately regulated, and correlative studies suggest that some may indeed contribute to clinical chemotherapy resistance.Current Opinion in Oncology 1995,7:19‐27