Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogenic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies. Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors (blasts) in the bone marrow and peripheral blood. Previously incurable, AML is now cured in approximately 35%–40% of patients younger than age 60 years old [1]. For those >60 years old, the prognosis is improving but remains grim. Recent studies have revealed that the disorder arises from a series of recurrent hematopoietic stem cell genetic alterations accumulated with age. Using deep sequencing techniques on primary and relapsed tumors, a phenomenon called clonal evolution has been characterized with both founding clones and novel subclones, impacting the therapeutic approach. Despite an increased understanding of AML biology, our efforts to this point in changing treatment strategy have been disappointing. In this review, we discuss the current diagnostic and prognostic strategies, current treatment approaches and novel therapies critical to AML management. Morphologically, AML blasts vary in size from slightly larger than lymphocytes to the size of monocytes or larger. The nuclei are large in size, varied in shape and usually contain several nucleoli. AML blasts express antigens found also on healthy immature myeloid cells, including common differentiation (CD) markers CD13, CD33 and CD34 [3]. Other cells markers are expressed depending on the morphological subtype of AML and stage of differentiation block such as monocytic differentiation markers (CD4, CD14, CD11b), erythroid (CD36, CD71) and megakaryocytes markers (CD41a and CD61). On occasion, AML blasts also co-express antigens restricted to T or B cell lineages including Terminal deoxynucleotidyl transferase (TdT), Human leukocyte antigen-antigen D related (HLA-DR), CD7 and CD19.