Hepatoblastoma (HB) is the most common primary liver malignancy in children, with an estimated incidence of 1.7 cases per million [1]. Hepatocellular neoplasm, not otherwise specified (HCN, NOS) is a provisional category to include malignant liver tumors, with histologic features of both HB and hepatocellular carcinoma (HCC), more frequently seen in children older than 5 years of age [2]. Standard management includes primary resection or chemotherapy followed by resection with a 3-year survival rate of 91% for standard-risk tumors [3]. High-risk cases are determined by pretreatment extent of disease (PRETEXT), age of diagnosis, levels of alpha-feto protein (AFP), vascular invasion, tumor rupture, extrahepatic extension of disease, multifocality of tumor, and metastases [24]. Patients that have high-risk disease have a lower 3-year survival of 65% [4]. High-risk cases require aggressive chemotherapy, leading to significant short and long-term complications, including deafness, cardiotoxicity, and renal toxicity [5], [6], [7]. Advances in targeted therapy are limited to the availability of representative samples for laboratory studies and tumor models. Few cell lines, such as HepG2, Huh-6, and HepT1, are available for experimental studies [8], [9], [10]. Earliest animal models were generated by subcutaneous injection of fresh patient-derived tumor cells in the back of female nude (Balb/c nun/nu) mice [8]. These subcutaneous murine models had several advantages, such as ease of access to monitor tumor growth and sampling for various experimental studies. However, they did not recapitulate the tumor microenvironment or show distant metastasis. This was followed by models generated with splenic [9] and intrahepatic [10], [11] injections of widely available cell lines. Both methodologies were successful in the development of intrahepatic tumors with the appropriate microenvironment. Splenic models typically resulted in small, multifocal nodules without a dominant mass, making it challenging to quantify the tumor burden and to study the effects of chemotherapy. Intrahepatic injection models did result in a dominant mass and, among other things, showed the ability to study drug toxicities in the context of impaired hepatic clearance due to tumor-related biliary obstruction – which was not possible in other models listed above. Recent developments in patient-derived xenograft (PDX) models are attempting to bridge this gap, leading to the identification of several novel candidate drugs for therapy-resistant tumors [12]. Limited studies have shown PDX models to be representative of original patient tumor samples with respect to histology and genetics [13]. However, the same report mentions that 12 out of 51 models (23.5%) showed discordance between the patient and the PDX histology with the PDX model mostly or exclusively representing the undifferentiated component in cases of rhabdomyosarcoma and nephroblastoma. Our study compared the histomorphologic and immunophenotypic profile of paired patient and corresponding PDX models of pediatric malignant liver tumors in order to evaluate and validate the models for future preclinical studies.