Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after curative treatment of early-stage HCC tumor, the carcinogenic microenvironment persists in the remnant diseased liver and supports development of de novo HCC tumors (de novo HCC recurrence). Therefore, prevention of HCC development in patients at risk of not only first primary but also second primary HCC tumors is theoretically the most impactful strategy to improve patient prognosis. However, no such therapy has been established to date. One major challenge is identification of clinically relevant targets, which can be achieved by utilizing the reverse-engineering strategy of chemoprevention discovery, integrating omics information from clinical cohorts with completed follow-up for cancer development. Clinical and experimental studies have suggested etiology-specific and generic candidate HCC chemoprevention strategies, including statins, antidiabetic drugs, selective molecular targeted agents, and dietary and nutritional substances. Clinical testing of the candidate compounds can be cost-effectively performed by combining it with HCC risk biomarker evaluation to specify the target patient population most likely benefit from the therapy. Non-toxic, generic agents will have broad clinical applicability across the diverse HCC etiologies and clinical contexts, and are expected to substantially improve the still dismal prognosis of HCC.