Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various strategies. alpha-fetoprotein (AFP) and liver ultrasonography (US) are the most widely used tools. AFP sensitivity and specificity depend on the cut-off value chosen. In cirrhotic patients, using a cut-off level of 20 ng/mL, sensitivity is only around 60% and positive predictive value ranges from 9% to 50%, depending on HCC prevalence. Sensitivity and specificity are much higher (94.1% and 99.9%, respectively) in hepatitis B carriers, but positive predictive value is only 5%. The performance of US as a screening tool varies widely depending on the experience of the examiner and the technology used. Recent studies generally indicate a 60% sensitivity or higher, a specificity greater than 90%, and a positive predictive value of 70%. The cost effectiveness of screening strategies using AFP, US, or both have been estimated retrospectively or using decision models. In general, HCC screening using both AFP and US appears to be of borderline cost effectiveness or not cost effective at all. Based on the estimated HCC doubling time, the recommended screening interval is 6 months, although a 1-year interval seems as effective. Currently, HCC screening with AFP only is not recommended except when US is either not available or of poor quality. US seems more efficient as a screening tool. Pathology assessment of liver explants in living-donor transplantation programs will provide more precise and reliable information regarding the value of AFP and US as HCC screening tools.