First-line chemotherapy treatment in acute-myeloid leukemia patients usually consists of a combination of cytarabine (ara-C) and an anthracycline. These regimens induce complete response (CR) rates in 65-80% of newly diagnosed AML patients. However, clinical outcome is unsatisfactory, as most of the patients who achieve a CR will relapse within 2 years from diagnosis, often with resistant disease and poor response to subsequent therapy. Thus, understanding the factors which contribute to the emergence of chemoresistant leukemic cells is essential to improve outcome in patients suffering from this disease. In this review, we highlight the current knowledge concerning the cellular mechanisms of resistance to ara-C. We also discuss possible strategies that may be used to overcome such resistance. Efforts to increase intracellular levels and DNA incorporation of phosphorylated ara-C using pronucleotides of ara-C are very promising. Ara-C combined with agents modulating apototic responses are expected to provide additional benefit. In the same way that combination chemotherapy has provided curative treatment of AML, a multifactorial approach of ara-C resistance should allow significant progress in the treatment of currently chemoresistant disease.