Akin to the introduction of tyrosine kinase inhibitors to Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), pediatric-based asparaginase-heavy approaches have revolutionized the treatment of young adults with the Philadelphia chromosome-negative subset the past decades. Once again, we are approaching a new era. An era of precision medicine with immunotherapy and other molecularly targeted treatments that offers unique opportunities to customize treatment intensity with or without hematopoietic stem cell transplantation, reduce the burden of toxicities, and combat persistent residual disease. Recently approved agents for refractory/relapsed B-cell precursor ALL include the chimeric antigen receptor-modified T-cells, the anti-CD22 monoclonal antibody-drug conjugate, inotuzumab ozogamicin, and the bispecific anti-CD19 T-cell engager, blinatumomab. These agents are expected to move widely into the frontline setting along with the proteasome inhibitors, bortezomib and carfilzomib, as well as tyrosine kinase inhibitors for Philadelphia-like rearrangements that are especially frequent among young adults. To this add the BH3 mimetics, venetoclax and navitoclax, which are being widely explored in refractory/relapsed as well as frontline settings for B- and T-cell ALL. The promising anti-CD38 monoclonal antibody, daratumumab, is entering the scene of refractory/relapsed T-ALL, whereas the old purine analogue, nelarabine, is being evaluated in a new upfront setting. This review focuses on 2 main questions: How do we optimize frontline as well as salvage ALL treatment of young adults in the 2020s? Not least, how do we address the current burden of serious toxicities unique to young adults?