Treatment of acute leukemia has evolved rapidly over the past 10 years. Moreover, the role of hematopoietic stem cell transplantation (HSCT) in such treatments has been changing. With the refinement of molecular-targeted therapy and other new modalities, HSCT is no longer the only curative option for leukemia. Nowadays, HSCT is being incorporated into the comprehensive scheme of leukemia treatment and is being compared to other treatment options. This was made possible through the effort to decrease nonrelapse mortality associated with HSCT to levels comparable with those of other modalities. In this review, we will particularly focus on transplantation in patients with aggressive leukemia and graft failure and discuss the role of conditioning regimens for HSCT in the new era of targeted therapy.