Cancer is the second most common cause of deaths worldwide after noncommunicable diseases. Hepatocellular carcinoma (HCC) is the fourth most deadly type of cancer worldwide. The reasons for this high rate of mortality are linked to the heterogeneity of HCC, late detection, and development of resistance to therapies. This chapter focuses on drug resistance in HCC. This chapter briefly explains the molecular signaling pathways and their role in drug resistance. This chapter further discusses cancer stem cells, stem cell markers, signaling pathways and transcription factors that regulate stem cell-mediated drug resistance in HCC. © 2022 Elsevier Inc. All rights reserved.