Advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) have not yet led to major improvements in disease-free and overall survival of adults with this disease. Only about one-third of those between ages 18-60 who are diagnosed with AML can be cured; disease-free survival is rare and current therapy devastating in older adults. In this chapter, challenges in the management of the adult with AML are discussed, including ongoing questions concerning the optimal choice of induction and postremission therapy such as the rationale for and role of allogeneic and autologous stem cell transplantation in a variety of settings, the special considerations pertaining to the older patient, and the development of new, so-called targeted therapies. In Section I, Dr. Richard Stone reviews state-of the-art therapy in AML in the era of change from a morphological to a genetically based classification system. Questions being addressed in ongoing randomized cooperative group trials include anthracycline dose during induction, the efficacy of drug-resistance modulators, and the utility of pro-apoptotic agents such as the anti-bcl-2 antisense oligonucloetide. Developmental therapeutics in AML include drug resistance modulation, anti-angiogenic strategies, immunotherapy, and signal transduction-active agents, particularly the farnesyl transferase inhibitors as well as those molecules that inhibit the FLT3 tyrosine kinase, activated via mutation in 30% of patients. In Section II Dr. Margaret O'Donnell discusses the role of stem cell transplantation in AML. Several advances including expanded donor pools, the movement toward peripheral blood stem cell collection, newer immunosuppressive drugs and antifungals, and particularly the advent of nonmyeloablative transplant have made the allogeneic option more viable. The subset-specific role for high-dose chemotherapy with autologous stem cell support and/or for allogeneic transplant in AML patients in first remission is outlined. Although preconceived notions about the role of transplant abound, the clinical data supporting a risk-adapted approach are covered. Finally, guidance concerning the use of nonmyeloablative or reduced-intensity allogeneic transplantation is provided. In Section III Dr. Mikkael Sekeres reviews the approach to the older patient with AML. Unique biological and therapeutic considerations make AML in this age group a vastly different disease than that in younger adults. The outcome data, including the role of specific anthracylines, hematopoietic growth factors, and drug-resistance modulators, are summarized. Communicating with older adults with AML and their families regarding selection of the optimal treatment strategy, often a stark choice between induction chemotherapy and palliative care, is covered.