This chapter examines the controversy surrounding diagnostic liver biopsy in patients with cirrhosis showing characteristic imaging features of hepatocellular carcinoma (HCC). The development of highly specific imaging algorithms, particularly the Liver Imaging Reporting and Data System (LI-RADS), has enabled non-invasive diagnosis of HCC in many cases. A selective biopsy strategy is discussed, highlighting its advantages in avoiding potential complications such as bleeding and tumor seeding. However, this approach limits the availability of tumor tissue for molecular characterization, which is increasingly relevant for personalized treatment strategies. The chapter presents arguments for both selective and routine biopsy approaches, considering diagnostic accuracy, patient safety, and the evolving landscape of targeted therapies. It concludes by proposing a balanced strategy: maintaining selective biopsy for most cases while considering tissue sampling in cases of diagnostic uncertainty or advanced HCC where molecular profiling could guide systemic therapy. The potential of emerging “liquid biopsy” techniques is also addressed as a future direction that may further refine the approach to HCC diagnosis and characterization.