To determine the role of screening and to screen in a cost-effective manner, it is important to define the high-risk patient population that is most likely to benefit from screening and to identify a readily available diagnostic modality that is sensitive, specific, and inexpensive. Moreover, to have a major effect on the outcome of hepatocellular carcinoma, the test should be applicable in the majority of high-risk subjects. Herein, we identify the high-risk patient population, discuss various diagnostic modalities, and recommend a practical and cost-effective strategy for screening.