Modern treatments and supportive care regimens for acute myeloid leukemia have produced some cures of what was once a uniformly fatal disease. To enhance the cure rate, intense efforts are now being put forth to understand the mechanisms of resistance to chemotherapeutic regimens that actually arise in clinical cases of acute myeloid leukemia, and to develop ways and means to circumvent such resistance. This review focuses on such efforts involving daunorubicin and cytarabine, the two most effective agents currently available for treatment of the disease. Most current published studies of daunorubicin have focused on detecting the classic form of multidrug resistance. For cytarabine, pharmocologically directed treatment approaches and enhancement of cytarabine leukemic cell kill by increasing the distribution of cells in S-phase and manipulating cellular cytarabine transport are currently under investigation.