The diagnosis of hepatocellular carcinoma (HCC) is based mainly on serological tumor markers, such as alpha-fetoprotein, L3% fraction thereof and PIVKA-II, and imaging modalities. These are not correlated but are complementary. Hence, a combination designed to take advantage of the characteristics of each needs to be worked out. First, it is necessary to identify the patients at high risk for developing HCC, such as those with chronic hepatitis or liver cirrhosis, and in the follow-up conduct regular check-ups for serological tumor markers. Those testing positive for any marker are at the highest risk for developing HCC, even when imaging fails to disclose any space-occupying lesions. Following these high-risk patients, in concert with imaging, enables accurate evaluation of the efficacy of therapies for HCC. Since serological tumor markers can signal the development of HCC earlier than any other laboratory test, they offer an excellent means of identifying relapsing HCC. Equally important in the management of patients with HCC are biological indicators for malignancy, selection of therapeutic interventions and prediction of the outcome.