Despite survival gains over the past several decades, adolescent and young adult (AYA) patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) demonstrate a consistent survival disadvantage. The AYA population exhibits unique disease and host characteristics, and further study is needed to improve their outcomes. This review will highlight distinctive aspects of disease biology in this population, as well as salient treatment-related toxicities including osteonecrosis, pancreatitis, thromboembolism, hyperglycemia, and infections. The impact of obesity and differences in drug metabolism and chemotherapy resistance will also be discussed, as well as optimal treatment considerations for the AYA population.