Traditional treatment regimens for adult acute lymphoblastic leukemia, including allogeneic hematopoietic cell transplantation, result in an overall survival of approximately 40%, a figure hardly comparable with the extraordinary 80% to 90% cure rate currently reported in children. When translated to the adult setting, modern pediatric-type regimens improve the survival to approximately 60% in young adults. The addition of tyrosine kinase inhibitors for patients with Philadelphia chromosome-positive disease and the measurement of minimal residual disease to guide risk stratification and postremission approaches has led to additional improvements in outcomes. Relapsed disease and treatment toxicity-sparing no patient but representing a major concern especially in the elderly-are the most critical current issues awaiting further therapeutic advancement. Recently, there has been considerable progress in understanding the disease biology, specifically the Philadelphia-like signature, as well as other high-risk subgroups. In addition, there are several new agents that will undoubtedly contribute to additional improvement in the current outcomes. The most promising agents are monoclonal antibodies, immunomodulators, and chimeric antigen receptor T cells, and, to a lesser extent, several new drugs targeting key molecular pathways involved in leukemic cell growth and proliferation. This review examines the evidence supporting the increasing role of the new therapeutic tools and treatment options in different disease subgroups, including frontline and relapsed or refractory disease. It is now possible to define the best individual approach on the basis of the emerging concepts of precision medicine.