Resistance to chemotherapy in acute myeloid leukaemia is a major obstacle to a successful outcome for many patients. Often, there is resistance against a broad range of drugs due to multiple, simultaneously active processes. These mechanisms include effects on drug influx and efflux, drug activation/inactivation, DNA repair mechanisms, altered response of end targets, an altered haematopoietic microenvironment and dysfunctional apoptotic pathways. This article reviews the factors that determine leukaemic cell chemosensitivity and discusses the potential for rationally guided therapy.