Hepatocellular carcinoma (HCC) remains a global health challenge, with an estimated incidence of >1 million cases by 2025. In spite of several drugs being available for its treatment, it remains the fourth most frequent cause of cancer-associated mortality globally. This is attributed to lack of targeted drugs and also a high variability in treatment response of the available drug regime A possible explanation for the differential response of these drugs in patients with HCC is the presence of intratumor and interpatient drug response heterogeneity. Several in vitro and in vivo models have been employed to study liver cancer pathogenesis and drug responses. In vitro techniques include the use of tumor cell lines and organoids. Talking specifically about organoids, they are three-dimensional (3D) cell cultures mostly from tissue-resident or embryonic stem cells (one or multiple) that are grown on hydrogels along with defined growth factors. These mini-organs closely resemble the in vivo tumor microenvironment and are being increasingly used to study the molecular mechanisms associated with HCC carcinogenesis and also examine the therapeutic efficacy of anti-tumor therapies. The culturing and expansion of normal liver organoids was first achieved by Huch et al with liver-resident mouse Lgr5+ liver stem cells. Till date, liver organoids have been derived from several cellular sources like adult stem cells (ASCs), induced pluripotent stem cells (iPSCs), primary hepatocytes (PHs) and primary cholangiocytes (PCs). During the process of liver organoid formation, the starting cell population begins to assemble and spatially arrange itself under the guidance of cell-intrinsic and extrinsic signals. Many organoid derivation protocols also involve the co-culturing of the stem cells with one or more supporting cells to facilitate the self-organization and differentiation of the stem cell. Addition of supporting cells allows all the cells to arrange themselves into a precise organ-specific architectural arrangement. For example, culture of liver organoids from  iPSC-derived hepatic endoderm cells (iPSC-HEs) has been shown in the presence of supporting cells like mesenchymal stem cells (MSCs) and umbilical cord-derived endothelial cells (HUVECs). The addition of supportive cells for heterotypic interactions helps in maintaining the viability, morphology, and function of the cultured organoids. Long-term tumor organoid cultures have also been derived from patients with primary liver cancer and propagated for more than one year in culture. The features of human liver tumor organoids closely resemble human liver tumor tissues. Several novel biomarkers of HCC have been identified using these models. Drug treatment of  tumor organoids have given variable results in the same patient as well as in different patients indicating the presence of intratumor heterogeneity. Thus patient-derived organoids may not only serve as excellent models to study mechanisms underlying HCC initiation, development and pathogenesis but also enable personalized treatments for patients with HCC in the years to come.