Next-generation sequencing (NGS) has transformed the diagnostic and therapeutic landscape of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). These tumors are molecularly heterogeneous diseases that require comprehensive genomic profiling for optimal clinical management. In HCC, recurrent alterations include TERT promoter mutations (50–60%), TP53 mutations (40–50%), and CTNNB1 mutations (20–35%), with distinct morphological and prognostic features. Cholangiocarcinoma molecular profiling reveals anatomical-specific patterns, with small duct intrahepatic tumors harboring targetable FGFR2 fusions (10–15%) and IDH1/IDH2 mutations (15–25%), while large duct tumors predominantly show KRAS and TP53 alterations. Recent advances have identified actionable alterations in approximately 40% of cholangiocarcinomas, leading to FDA-approved targeted therapies including FGFR inhibitors (pemigatinib, infigratinib, futibatinib) and IDH1 inhibitors (ivosidenib). Technical considerations include ensuring adequate tumor cellularity, optimizing tissue handling and allocation for molecular testing, and selecting the sequencing platform according to tumor subtype. Liquid biopsy offers complementary approaches when tissue sampling is limited, with detection rates varying by tumor burden.