Acute Myeloid Leukemia (AML) is a highly aggressive clonal hematopoietic disorder that has been managed with largely unchanged treatment protocols for the past decades. Although conventional chemotherapy bears the potential to cure some AML patients, the course of the disease is frequently fatal despite treatment highlighting the need for novel therapeutic concepts. Recent progress in genetic technologies significantly furthered our understanding of the molecular events leading to the disease, but these advances have not yet been successfully translated into improved treatment outcomes. Here, we review some of the new promising targets expressed by leukemic blasts, including important signaling pathways involved in AML stem/progenitor cell maintenance and drug resistance. We furthermore discuss novel targeted therapies in pre-clinical and clinical development thereby focusing on new compounds targeting receptor and non-receptor tyrosine kinases, farnesyltransferase proteins, and epigenetic modifiers.