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Acute myeloid leukemia (AML) is characterized by extensive clinical and biological heterogeneity. Despite vast advances in understanding the molecular pathology in AML during the last two decades few new AML therapeutics have been approved by the European Medicines Agency. Since 2005 only the epigenetic modulators decitabine and azacytidine, as well as histamine (plus interleukin- 2) have been approved against AML. None of these have outstanding efficiency, and decitabine and azacytdine have only been incorporated in frontline therapy of AML with limited enthusiasm. The majority of AML patients are frail and elderly, and lack of mild but effective agents for this patient cohort constitutes a major unmet need as overall survival remains poor. Along with the recent advancements in the molecular characterization of AML, numerous targeted therapies have been tested in clinical trials. In this review, we discuss the biological rationale for a selection of these novel therapeutic approaches, including epigenetic modifiers, agents targeting signalling pathways and inhibitors of nuclear-cytoplasmic shuttling. Further we discuss some of the possible shortcomings in current trial design that could explain the apparent incoherence between our improved biological knowledge and the lack of progress in therapy development of AML.