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Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. Our current understanding of the unique biological/genomic characteristics of AYA cancers is limited. However, there has been some progress that has provided clues about the biology of AYA cancers. We here review the latest findings in the area of AYA cancer biology and discuss what is required to advance the field for the more effective treatment of this patient population.