Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after complete HCC tumor resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumors, which progress into incurable, advanced-stage disease in the majority of patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, practice guideline-recommended “one-size-fits-all” HCC screening for early tumor detection is utilized in less than 20% of the target population, and performance of screening modalities, i.e., ultrasound and alpha-fetoprotein is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations such as chronic hepatitis C after viral cure and non-cirrhotic non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailored HCC screening for individual patients to maximize its cost-effectiveness and optimize allocation of limited medical resources. Several etiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalized chemoprevention targeting high-risk patients to achieve precision HCC prevention and substantially improve the dismal prognosis of HCC.