The role of liver biopsy in the diagnosis of hepatocellular carcinoma (HCC) has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis. In fact, in the diagnostic algorithm for this tumor, histology is currently relegated to controversial cases. Furthermore, the risk of complications, such as tumor seeding and bleeding, as well as inadequate sampling have further limited the use of liver biopsy for HCC management. However, there is growing evidence of prognostic and therapeutic information available from microscopic and molecular analysis of HCC and, as the information content of the tissue sample increases, the advantages of liver biopsy might modify the current risk/benefit ratio. We herein review the role and potentiality of liver biopsy in the diagnosis and management of HCC. As the potentiality of precision medicine comes to the management of HCC, it will be crucial to have rapid pathways to define prognosis, and even treatment, by identifying the patients who could most benefit from target-driven therapies. All of the above reasons suggest that the current role of liver biopsy in the management of HCC needs substantial reconsideration.