This chapter addresses the prediction and management of relapsed and refractory acute myeloid leukemia (AML) patients. In current standard therapy for AML, 20–30% of younger and up to 50% of patients >60 years will have refractory disease and not respond to induction therapy. Among patients who achieve complete remission (CR), long-term disease-free survival (DFS) rates are only around 30%. The risk of relapse is highest early after achievement of CR and declines with time. Both patient- and disease-specific factors determine outcome. Pretreatment karyotype remains the most important prognostic factor regarding achievement of remission, risk of relapse, and overall survival (OS). Disease relapse is a very important cause of treatment failure after transplant; most relapses occur within one year of transplant. Several prognostic indices have been devised to more accurately predict outcome for patients in first relapse. There is no standard salvage regimen for adults with relapsed or refractory AML. The principal goal remains procurement of a second remission followed by HPCT (progenitor cell hematopoietic cell transplant). Without it, prognosis is very poor. Should transplant not be an option, or in refractory cases, investigational therapies should be seriously considered.