Acute myeloid leukemia (AML), the second most common type of leukemia in children, is a heterogeneous disease known to be caused by genetic, epigenetic, and transcriptional changes, predominantly somatic and germline abnormalities. Despite significant improvement of overall survival rates, the prognosis of pediatric AML remains unfavorable in comparison with acute lymphoblastic leukemia (ALL), especially in relapsed or refractory settings. The current status and future directions are focused on establishing an accurate diagnosis and treatment strategies based on the genomic background. Next-generation sequencing (NGS) technologies enable a broader understanding of the basis of the disease for the purpose of determining pathology-associated mutations and additional prognostic biomarkers in pediatric AML. This review focuses on providing an overview of the known and possible prognostic factors, as well as genetic landscape of pediatric AML patients and how it can be used to accurately differentiate and risk stratify patients. It also presents potential candidate modifications for risk adjustment and targeted therapy. Furthermore, we describe in this article a case of a 22-month-old male patient with relapsed M5 high-risk group (HRG) AML with complex karyotype. Due to belonging to the HRG, as well as unsatisfactory chemotherapy response, the patient underwent matched unrelated donor (MUD) stem cell transplantation (SCT).