Acute lymphoblastic leukemia (ALL) is characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. The incorporation of pediatric-type regimens has improved survival in young adults, and the incorporation of tyrosine kinase inhibitors for patients with Philadelphia chromosome-positive disease has led to further improvements in outcomes. However, older patients often have poor-risk biology and reduced tolerance to chemotherapy, leading to lower remission rates and overall survival. Regardless of age, patients with relapsed or refractory ALL have extremely poor outcomes. The advent of next-generation sequencing has facilitated the revolution in understanding the genetics of ALL. New genetic risk stratification together with the ability to measure minimal residual disease, leukemic blasts left behind after cytotoxic chemotherapy, has led to better tools to guide postremission approaches-that is, consolidation chemotherapy or allogeneic stem cell transplantation. In this article, we discuss the evolving and complex genetic landscape of ALL and the emerging therapeutic options for patients with relapsed/refractory ALL and older patients with ALL.