The management of oncological malignancies has significantly improved over the last decades. In modern medicine, new concepts and trends have emerged paving the way for the era of personalized and evidence-based strategies adapted to the patients’ prognostic variables and requirements. Several challenges do exist that are encountered during the management, including the difficulty to assess chemotherapy response with certainty. Having known that neoadjuvant chemotherapy might be the only solution for a proportion of patients with tumors that are unresectable at diagnosis, emergence of strategies that use risk group-directed therapy became an integral part in the management of oncological malignancies. Tumor histopathological change post neoadjuvant chemotherapy is one of the most important predictors of management outcome and is being used in many chemotherapy protocols as an essential determinant of the most suitable postoperative chemotherapy regimen. Bone tumors are the classic models of this approach; however, other childhood solid tumors show significant variations in outcome as a result of tumor histopathological response to neoadjuvant chemotherapy. The aim of this review is therefore to summarize the significance of histopathological responses seen after neoadjuvant chemotherapy in childhood solid tumors. Moreover, it suggests that the effect on tumor histopathology through modifying neoadjuvant chemotherapy and, on the other hand, toxicities from intensifying adjuvant chemotherapy might either necessitate the change of a number of arm groups in different protocol regimens or include newer chemotherapeutic agents adjuvantly for better outcome and lesser toxicities in poor tumor histopathological responders.