Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, the majority of patients die after relapse or of complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed, especially for elderly patients. An indispensable prerequisite to investigate tailored approaches for AML is the recent progress in the understanding the molecular features that distinguish leukemia progenitors from normal hematopoietic counterparts and the identification of a variety of dysregulated molecular pathways. This in turn would allow the identification of tumor-specific characteristics that provide a rational basis for the development of more tailored, and hence potentially more effective and less toxic, therapeutic approaches. In this review, we describe some of the signaling pathways that are aberrantly regulated in AML, with a specific focus on their pathogenetic and therapeutic significance, and we examine some recent therapies directed against these targets, used in clinical trial for relapsed patients or unfit for conventional chemotherapy.