Acute Myelogenous Leukemia (AML) is a malignant disease of the hematopoietic cells, characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow failure and impaired normal hematopoiesis. AML comprises a heterogeneous group of malignancies, characterized by a combination of different somatic genetic abnormalities, some of which act as events driving leukemic development. Studies carried out in the last years have shown that AML cells invariably have abnormalities in one or more apoptotic pathways and have identified some components of the apoptotic pathway that can be targeted by specific drugs. Clinical results deriving from studies using B-cell lymphoma 2 (BCL-2) inhibitors in combination with standard AML agents, such as azacytidine, decitabine, low-dose cytarabine, provided promising results and strongly support the use of these agents in the treatment of AML patients, particularly of elderly patients. TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are frequently deregulated in AML patients and their targeting may represent a promising strategy for development of new treatments. Altered mitochondrial metabolism is a common feature of AML cells, as supported through the discovery of mutations in the isocitrate dehydrogenase gene and in mitochondrial electron transport chain and of numerous abnormalities of oxidative metabolism existing in AML subgroups. Overall, these observations strongly support the view that the targeting of mitochondrial apoptotic or metabolic machinery is an appealing new therapeutic perspective in AML.