Abstract Unlike younger adults with acute lymphoblastic leukemia (ALL), older adults are rarely cured due to a combination of intrinsic disease resistance and treatment-related toxicities. Novel therapeutics such as inotuzumab ozogamicin, blinatumomab, venetoclax, and ABL kinase inhibitors have high activity in ALL and are well tolerated by older adults. Frontline treatment regimens for older adults using novel therapeutics with reduction or omission of conventional chemotherapy are being developed with early results demonstrating high remission rates and lower toxicity, but long-term efficacy and toxicity data are lacking. Collaboration between academic and pharmaceutical stakeholders is needed to develop clinical trials to define the optimal treatment regimens for older adults with ALL.