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Simple Summary Around 90% of children diagnosed with acute lymphoblastic leukemia are long-term survivors due to the efforts made in the last decades to tailor the chemotherapy protocols, which is not the case for the adult population. This literature review proposes to bring together all the relevant data to answer the ardent question: why the results in adults, adolescents and young adults are not nearly as good as those obtained in children? Abstract It is a new and exciting time for acute lymphoblastic leukemia (ALL). While nearly 50 years ago, only one in nine children with ALL survived with chemotherapy, nowadays nearly 90% of children have a chance of long-term survival. Adults with ALL, as well as the special category of adolescents and young adult (AYA) patients, are catching up with the new developments seen in children, but still their prognosis is much worse. A plethora of factors are regarded as responsible for the differences in treatment response, such as age, ethnicity, disease biology, treatment regimens and toxicities, drug tolerance and resistance, minimal residual disease evaluation, hematopoietic stem cell transplantation timing and socio-economic factors. Taking these factors into account, bringing pediatric-like protocols to adult patient management and incorporating new agents into frontline treatment could be the key to improve the survival rates in adults and AYA.