Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality in China. In recent years, the application of targeted therapy and immunotherapy has improved the survival rate of HCC patients. However, a significant difference in treatment response is observed among HCC patients due to tumor heterogeneity and a lack of biomarkers to predict efficacy. The advance in proteogenomics-centered multi-omics studies and the development of high-throughput drug screening platforms will help to develop new clinical treatment strategies for HCC and new methods for predicting the efficacy of precision medication, thereby realizing personalized precision diagnosis and treatment.